Defending champions England are the team to beat as they look to extend their 14-game winning streak but Eddie Jones has a number of injury problems to contend with in his forward pack.
The loss of the Vunipola brothers diminishes England's ball-carrying threat while the absence of Chris Robshaw and doubts over James Haskell means they could be without their first-choice back row against France.
England face a difficult start against France and Wales but have developed an ability to grind out victories, even when faced with a numerical disadvantage and struggles at the set piece.
Jones will hope Nathan Hughes can fill into Billy Vunipola's sizeable shoes and that Ben Youngs can rediscover the excellent form he produced during the autumn.
Owen Farrell has been erratic off the tee of late but along with George Ford, they will punish any teams that cough up possession cheaply. Competition for places is fierce in the back division and Jones has some big calls to make on the wings.
Dylan Hartley has been retained as captain and he will be intent on repaying the faith shown in him by Jones, as well as catching Warren Gatland's eye.
It is not inconceivable that England will claim bonus-point wins in their three Twickenham fixtures, while capitalising on Wales' six-day turnaround in round two. That would put them in pole position when they travel to Dublin on the final day with a tier-one record 19th victory in their sights.
Player to watch
Alex Lozowski impressed at fly-half during Owen Farrell's absence at the beginning of the season and outlined his versatility with some eye-catching displays at full-back.
The Saracen possesses a fine kicking game, soft hands and runs some fantastic attacking lines. Given the chance he could light up the tournament.
Six Nations squad
Forwards: Nathan Catt, Jack Clifford, Dan Cole, Charlie Ewels, Ellis Genge, Jamie George, Teimana Harrison, Dylan Hartley, James Haskell, Nathan Hughes, Maro Itoje, George Kruis, Joe Launchbury, Courtney Lawes, Joe Marler, Matt Mullan, Kyle Sinckler, Tommy Taylor, Mike Williams, Tom Wood.
Backs: Mike Brown, Danny Care, Elliot Daly, Owen Farrell, George Ford, Jonathan Joseph, Alex Lozowski, Jonny May, Jack Nowell, Henry Slade, Ben Te'o, Anthony Watson, Marland Yarde, Ben Youngs.