Shrewsbury Town, who take on Manchester United on Tuesday morning (AEDT), are the only team left from the bottom two divisions, with Premier League sides accounting for 11 of the 16.
Here, Press Association Sport looks at some of the talking points arising from the ties.
BIG FISH DOMINATE
The natural order of the Premier League may have been turned upside down this season, but the favourites have been very much on top in the FA Cup. Leicester City and Liverpool, both of whom were beaten by Premier League opposition, are the only obvious absentees from the last 16, and the quarter-finals could feature exclusively top-flight teams. The stand-out fixture of the round pits Chelsea against Manchester City. Domestic cups represent the best chance of silverware for both teams in this most unusual of seasons so expect the clash to have extra spice. Shrewsbury, Hull City, Blackburn Rovers, Leeds United and Reading are flying the flag for the Football League.
FORMAT UNDER SCRUTINY
Reports this week have cast doubt on the future of the FA Cup in its current form. With teams feeling the calendar pressure more than ever, it has been suggested replays could be scrapped or the competition moved to midweek. Shrewsbury boss Micky Mellon this week said losing replays would 'kill' small clubs, for whom trips to Premier League giants in the cup offer a financial lifeline. Attendances at this weekend's ties are sure to be scrutinised as the Football Association mulls over the future of its flagship competition.
TOTTENHAM AT THE DOUBLE
It is not inconceivable that Tottenham Hotspur could be on for the double - or even treble with the UEFA Europa League. Mauricio Pochettino's men sit two points behind leaders Leicester in the Premier League and will be hot favourites to beat out-of-form Crystal Palace at White Hart Lane. Spurs had won their last seven games before a 1-1 draw at Fiorentina in the Europa League and could certainly claim to be the country's form team. Tottenham are eight-times winners of the FA Cup but have not had their hands on the trophy since 1991, while their wait for a league title goes all the way back to the double year of 1961.
DEJA VU AGAIN
For the third season in a row, Arsenal and Hull will do battle in the FA Cup, and the Tigers will be hoping to make it third time lucky. The pair met in the final in 2014, with Arsenal coming from two down to win in extra-time. Last season, they were paired together in the third round, this time goals from Per Mertesacker and Alexis Sanchez giving the Gunners a more comfortable victory. History is not on Hull's side given they have not beaten Arsenal in the competition since 1908. Arsene Wenger, meanwhile, will hope the tie is a good omen as his side aim to make it an FA Cup hat-trick.
VAN GAAL AND MARTINEZ SEEK CUP CHEER
Louis van Gaal's future at Manchester United has rarely been far from the headlines over the past few months and last weekend's defeat by Sunderland brought it into sharp focus once more. There has already been failure in the League Cup and UEFA Champions League, and defeat by Shrewsbury is surely unthinkable. Another manager hoping for a cup boost is Everton's Roberto Martinez after their brief upturn was ended by last weekend's home defeat against West Bromwich Albion. The Toffees have lost six times at home in the league so it is good news for them that they are away at AFC Bournemouth.