France, Ireland and Italy go in search of a first win in this year's championship, so what are the main talking points? We take a look here...
Will Ireland produce another slow start in Murrayfield?
Joe Schmidt will be spending much of this week searching for answers to Ireland's sluggish start in defeat against England.
The defending champions need to resurrect their campaign now against a buoyant Scotland with the concession of a try after just 90 seconds at the forefront of their minds from kick-off.
Schmidt revealed after the England game that he feared the worst given the eerie silence that swept the dressing room at the Aviva Stadium.
He said: "We were very quiet. I didn't sense the same kind of energy levels that I would've noticed in November when the All Blacks came.
"And if you don't have those energy levels and have that mental preparation done, it's pretty difficult to get a foothold back into the game.
"I didn't sense it. I didn't feel that - you almost get this vibrancy from the group, and we didn't quite have it."
With Robbie Henshaw making his first appearance since October, it wasn't a good time for Johnny Sexton and Conor Murray to be off-colour. Ireland must get back on track.
They are hanging onto second place in the world rankings, and after New Zealand head coach Steve Hansen warned they would face a different kind of pressure as the team to beat, Schmidt's men must show in Scotland they candle handle the weight of expectation.
Murrayfield presents a mental challenge and a chance for a blip to not become a crisis.
Will Gatland learn from his mistakes in Rome?
It is often said that some victories in sport are more down to luck than judgement, but in the opening 40 minutes in Paris, Wales didn't even give themselves the chance of benefiting from good fortune.
Bad handling, ill-discipline and poorly executed decisions gave France a 16-0 half-time lead, and Warren Gatland must accept that his experimental approach didn't really work if Wales are to create history at the Stadio Olimpico.
If Italy are defeated, they will match their all-time longest unbeaten run of 11 Tests, set between 1907 and 1910, but a combination of France's implosion and conditions is the reason why their current record is still intact.
Gatland knows that Ireland, England and Scotland will not be as generous as last Friday's opponents.
It is in the midfield where Gatland may look to shuffle the most, with Owen Watkin a possible replacement for Hadleigh Parkes, who has failed to kick on since his arrival on the international stage.
Then there is Gareth Anscombe, who epitomised Wales' tale of woe in the first half, his two missed tackles meaning it came as no surprise when he was hooked for Dan Biggar.
With Gareth Davies back at scrum-half, Biggar should now retain his place and both should be asked to show their big-game pedigree in Rome as though it were a Grand Slam decider.
The back-row might pick itself, but Gatland must learn from his mistakes elsewhere if he is to get the perfect Six Nations send-off.
Can England cope without Itoje?
"Maro's going to be the best lock in the world so it's a big loss, but we've got good depth." The words from Eddie Jones after England's bruising 32-20 win over Ireland encapsulated the dilemma.
A scan on Monday confirmed medial ligament damage, meaning Itoje will miss the matches against France and Wales but could return for the final rounds of England's title quest. In a World Cup year, Jones will surely err on the side of caution.
In Joe Launchbury, England have the resources to cover the Saracens lock's absence, which will almost certainly be felt against the French at Twickenham.
Itoje was instrumental in dominating the Irish pack, but Launchbury will now vie to replace him with Courtney Lawes, who impressed when coming off the bench at the weekend.
Twickenham will be rocking after England's bonus-point win over the holders, ending an eight-year wait for a try in the process at the Aviva as Jonny May, Elliot Daly and Henry Slade on two occasions emphatically put that to bed.
After the medial ligament damage to Itoje's knee, Jones highlighted the strength of character in his front five, but the French test will reveal how much the brutal contest in Dublin took out of this new-look Red Rose team.
If England can play without any noticeable drop-off in Itoje's absence, a possible third Six Nations title in four years will be in sight.
Can depleted Scotland prove their strength in depth?
Murrayfield has been a fortress for Scotland for some time now. Wales, England, France, Australia, Argentina and Ireland have all been vanquished in the three years since an away team left with a victory.
Ireland will have to significantly improve on their opening-weekend display if they are to end that run, but Scotland showed their brittle side after the casualty list grew against Italy.
After a blistering start, Gregor Townsend knows he will need a performance from his side throughout 80 minutes against a wounded Ireland.
Murrayfield will be a sell-out for a 12th consecutive game, and Stuart Hogg admitted that the side suffered a physical drop-off towards the end, allowing Italy to score three unanswered tries after Simon Berghan's sin-bin.
A 30-point lead resulted in just a 13-point victory, and they now look to replicate victory over Ireland in the corresponding fixture two years ago without Hamish Watson and John Barclay - and with Sam Skinner returning to his club for assessment on an ankle injury.
If the renaissance under Townsend will lead to a first championship since 1999, Scotland must show they can match the strength in depth of Ireland, England and Wales.
Townsend said after the win over Italy: "Scoring five tries is a credit to the players, but we know next week's challenge is huge. We have to get the focus right almost immediately. We'll reflect and learn what we need to do better."
Facing Schmidt's side will certainly heighten the senses and provide the ultimate litmus test of Scotland's progress.
Which France will turn up at Twickenham?
The simple headline 'Despair' on the front page of L'Equipe on Saturday morning said it all. The player ratings were equally damning as France continue to struggle to shake off their tendency to throw away matches.
Surrendering a 16-point advantage at home is the worst possible start to the year for Jacques Brunel's side, made all the more damaging given France's implosion and gift of two Welsh tries from glaring individual errors.
Yoann Huget and Sebastien Vahaamahina will be desperate to get back out on the field after their ludicrous mistakes, but Brunel is likely to drop the guillotine on those he deems as the biggest culprits.
Wales had been outplayed and beaten up by a revitalised France, before Huget went from hero to zero.
The winger has come out fighting, saying: "England have been our best friends for many years now. It is a game the public in France have been waiting for a long, long time. I suspect it's the same in England."
France lost it twice against Wales, allowing a 16-0 lead to slip only to get their noses in front with eight minutes remaining before Vahaamahina's moment of madness.
Without a win at Twickenham since 2006, Brunel has the consolation of being able to easily identify where improvement must surely come against Jones' side.
Morgan Parra missed three kicks, and the France head coach said: "Of course I'll take some positives because it feels like on the whole, we produced some good passages, against the best defence, at least in Europe, under pressure. I think we put them under more pressure than they did us."
Italy seek end to unwanted record
If only Conor O'Shea's side could always play against 14 men.
Three tries from Guglielmo Palazzani, Edoardo Padovani and Angelo Esposito after Berghan's sin bin demonstrated what Italy can do with a numerical advantage and with the pressure off.
O'Shea lamented the sweeping illness that afflicted his squad in the build up to the opening-day loss to Scotland while Palazzani was a late replacement for Tito Tebaldi, who was forced to withdraw in the warm up due to injury.
"We had a virus that went through a number of the guys," he said in his post-match press conference. "I nearly had to carry Guglielmo Palazzani off the plane on Thursday. He was so ill.
"When we lost Tito before the kick-off, Guglielmo had to play 80 minutes. You can't buy heart like that. These guys gave a huge amount against the odds."
Sergio Parisse made his 66th Six Nations appearance - setting a new competition record - but in welcoming Wales to Rome this weekend, the veteran No 8 will not be dwelling on his individual landmark.
The camp remains outwardly positive despite the wooden-spoon holders setting a new unwanted record at Murrayfield, their losing streak stretching now to 18 matches.
It was in Edinburgh four years ago that the Azzurri last won, but their 33-20 defeat last weekend means they have now surpassed France's record of 17 straight losses between 1911 and 1920 in the Five Nations.
Italy showed that in possession they can be dangerous and capable of scoring tries, and they will look to use the final 10 minutes of the Scotland defeat as a good base to work on ahead of facing Wales.