Victory for Ireland against Italy on Saturday - in the match that sees O'Driscoll become the world record holder for Test appearances - will see Joe Schmidt's men edge closer to a first RBS 6 Nations title since 2009.
Currently top by virtue of a superior points difference, Ireland know they will take some catching should they win their remaining two matches and O'Driscoll, who has won just a solitary RBS 6 Nations title, would like nothing more than to sign off with another.
Italy however, chalked up a first ever Championship win over Ireland last year and will be desperate to get their 2014 campaign underway having come so close against Scotland last time out.
The Scots meanwhile, are buoyant after banishing the gloom with that win in Rome and, back at Murrayfield, they fancy their chances against a France team licking their wounds after they were heavily beaten in Wales.
Back comes Kelly Brown to skipper the side, as well as No.8 David Denton, while Geoff Cross gets the chance from the off after coming on in Rome to sure up the wobbling scrum.
Francemeanwhile, have made sweeping changes. In total, there are seven new faces from the side in Cardiff - some injury-enforced, others due to lack of form or discipline.
Wesley Fofana, Yannick Nyanga and Dimitri Szarzewski are all out injured while Louis Picamoles is dropped for his reaction to his yellow card in the Millennium Stadium.
It means Sebastien Vahaamahina gets a rare outing in the back row, Brice Mach comes in at hooker and Maxime Mermoz makes his first appearance of the competition at inside centre.
Further changes see Damien Chouly get the nod at No.8, Alexandre Lapandry starts at flanker, Maxime Machenaud comes in at scrum-half while Maxime Medard returns on the left wing.
While defeat in Cardiff has rattled les Bleus, Wales are resurgent as they return to the place where it all began for Warren Gatland six years ago.
Gatland, in his first match in charge, took Wales to Twickenham and chalked up an unlikely victory and did so again two years ago.
Looking to do so once more, Wales have been boosted by the return of centre Jonathan Davies and second row Alun Wyn Jones, ensuring their starting XV features 11 of the side that defeated England 30-3 in Cardiff last year.
That defeat still lingers for England, who will have a far different look about themand are brimming with confidence following victories over Scotland and Ireland and who are seeking the Triple Crown.
They will be without Billy Vunipola and Stuart Lancaster is still waiting for a first victory over Wales but he'll be hoping home advantage proves pivotal in a match that neither side can afford to lose.