Wales will make the trip to Edinburgh in the early Saturday kick-off as they look to maintain their 100% record with a victory against a struggling Scottish outfit.
Later that day, England take on Italy as they hope to bounce back from a disappointing loss against Wales with a strong performance at Twickenham.
And Sunday’s flagship game sees Ireland take on France as both sides aim to finish the Championship strong.
With a host of PRO14 players suiting up for international action this weekend, here are the main talking points.
Stander and Byrne Return to boost Irish hopes
Munster’s CJ Stander returns to the Ireland team after a facial injury kept him out of the last two Guinness Six Nations fixtures.
The No.8, who started Ireland’s opening day loss to England, has been in and out of the Munster side this season, with his last appearance coming against Connacht Rugby in early January.
But Joe Schmidt clearly has faith in the 28-year-old as Ireland face a must-win game against France on Sunday.
Ireland will once again look to Munster’s Conor Murray, whose two tries and couple of penalties make him the nation’s top scorer this year.
Also making the cut is Leinster fly-half Ross Byrne, who could earn his third cap for Ireland as they look to pick up their third consecutive win.
The 23-year-old has been in good form for his club side, making 16 appearances and crossing the 100 point mark for the season in mid-February.
He scored an excellent try against Toyota Cheetahs last weekend before converting another two to secure a timely win – and he could make his Six Nations bow on Sunday.
Fellow try-scorer Kieran Marmion adds to the Connacht Rugby contingent as he gets back in the squad alongside Ulster’s Rob Herring.
Wales put faith in Ospreys’ Beard
Cory Hill’s untimely injury after an excellent performance in the win against England means Adam Beard will slot into the second row against Scotland on Saturday.
But Warren Gatland will hope the Ospreys star will continue his unbeaten streak in a Welsh shirt – the lock is yet to lose in 11 appearances for his nation.
He joins teammates George North, Justin Tipuric and Alun Wyn Jones – who captains Wales – in the starting XV.
Jake Ball is drafted in to fill Beard’s bench spot as Scarlets continue to represent the lion’s share of the national squad.
Bennetton duo return to XV
Sergio Parisse may be the most notable change to the Italian team to face England, but the Azzurri will also welcome back Round Three absentee Sebastian Negri.
The Bennetton lock missed the defeat to Ireland due to illness but will return to an Italian side looking for their first win of the Championship.
Meanwhile, Luca Bigi will get the nod at hooker as he makes his first start in this year’s Six Nations ahead of Leonardo Ghiraldini.
Teammate Tommaso Allan has been a bright spot in Italy’s sluggish campaign thus far as he has scored 16 points while Edoardo Padovani (Zebre) has crossed three times.