Seventy-four places separate the two sides in the Football League pyramid, but Tranmere have the home advantage as they look to pull off a giant-killing on Merseyside.
Tottenham's focus must switch from one part of Merseyside to another for this match as they shelve hopes of chasing down Liverpool to avoiding a shock exit at the hands of Tranmere.
Rovers have settled nicely back into Football League life following last summer's promotion from the National League, where they had spent three seasons following the end of their 94-year stay in the top four divisions.
Micky Mellon's men currently sit ninth in League Two, just three points off the playoff places having won 10 of their 26 outings so far, losing only seven - the joint-fourth lowest tally in the division.
Tranmere fans will be wary of getting too carried away considering the substantial playoff heartache they have experienced in the past - most noticeably losing in three successive post-season campaigns which could have taken them up to the Premier League.
An FA Cup night under the lights will evoke memories of happier times for Rovers as they look to rediscover a rich history of giant killings at the expense of Tottenham.
The 1999-2000 campaign saw Tranmere reach the final of the League Cup and the quarter-finals of the FA Cup, during which time they claimed the scalps of four Premier League sides over the two tournaments.
The Merseysiders went on to reach the quarter-finals of the FA Cup three times in the space of five years - and the fifth round in one of the other years - but they have not made it past this stage since that run came to an end in 2003-04.
Mellon's side have dispatched of lower-league opposition in their two previous rounds this season, although they needed replays on both occasions after initially drawing with Oxford City and then Southport.
The concern will be that both of those draws came at home, while their subsequent victories both came away, and it is now more than five years since Tranmere won an FA Cup game in front of their own fans.
The hosts are unbeaten in their last seven outings at Prenton Park across all competitions, though, and the atmosphere is sure to be red hot as they look to pull off a Roy of the Rovers-style victory.
Recent FA Cup form: DWDW
Recent form (all competitions): LWLWDD
Arsenal and Manchester United are the only clubs to have won the FA Cup more often than Tottenham, but you have to go back to 1991 for the last time they lifted the trophy.
It is far too long a drought for a club of such rich history in this tournament, and while their interests are still very much alive in every other competition, the prospect of FA Cup success will be very appealing to the Spurs fans.
A third-round game against League Two opposition represents a fairly kind start on paper, particularly considering that Spurs have progressed from 17 of their last 18 FA Cup ties against lower-league opposition.
Tottenham have now won 13 of their last 16 games across all competitions, losing just twice in that time, and they have scored 15 goals in their last four outings - due largely to the prolific streaks of Son Heung-min and Harry Kane.
The main danger for Spurs ahead of Friday's match may be complacency, then, while there is also the possibility that they could allow their minds to drift towards a huge week next week which sees them take on Chelsea in the first leg of their EFL Cup semi-final, and then Manchester United in the Premier League.
Pochettino and his players also have a vested interest in Thursday night's league clash between Manchester City and Liverpool having established themselves as genuine title challengers over the festive period.
There could be a six-point or a nine-point gap separating them from the Premier League leaders by the time they get underway at Prenton Park, then, but for now their focus must be firmly on cup duties with two matches to play before they are back in top-flight action.
Tottenham have lost just one of their last 13 away games across all competitions - scoring nine times in their last two - and that run includes a draw at Camp Nou, victory at the Emirates Stadium and hitting six goals at Goodison Park.
A trip to Prenton Park should not be too daunting for the Premier League outfit, then, although Pochettino may be quick to remind his side that they were held away at Newport County and Rochdale en route to the semi-finals of this competition last season.
Recent form (all competitions): WWWWLW
Pochettino is expected to make a string of changes with Chelsea awaiting them on Tuesday night, although injury problems do limit his options slightly.
Eric Dier, Jan Vertonghen, Victor Wanyama and Vincent Janssen all remain sidelined, while Mousa Dembele, Erik Lamela and Serge Aurier are major doubts for this one and are unlikely to be risked if they are not fully fit.
The likes of Paulo Gazzaniga, Juan Foyth, Ben Davies, Kyle Walker-Peters, Oliver Skipp and Fernando Llorente could all be in line to feature, while Georges-Kevin N'Koudou may also benefit from the rotation.
Tranmere do not have the luxury of such squad depth, and Mellon could name a full-strength side in an attempt to pull off an upset.
James Norwood has netted 16 goals in 25 league games to sit joint-top of the League Two scoring charts and is likely to be Tranmere's main hope of troubling the Tottenham backline.
Tranmere possible starting lineup:
Davies; Buxton, Ellis, Monthe, Ridehalgh; Caprice, McCullough, Harris, Smith; Norwood, Jennings
Tottenham possible starting lineup:
Gazzaniga; Walker-Peters, Sanchez, Foyth, Davies; Skipp, Winks; Sissoko, Alli, N'Koudou; Llorente
Head To Head
Spurs have never lost in eight previous meetings against Tranmere across all competitions, winning six of those and scoring 29 goals in the process.
The last three of those meetings have all seen Spurs run out 4-0 winners, most recently in the fifth round of this competition in February 2002, when Christian Ziege, Gus Poyet (2) and Teddy Sheringham were on the scoresheet for Spurs at White Hart Lane.
That is one of two occasions on which Tottenham have knocked Tranmere out of the FA Cup, also doing so in 1952-53 when they ran out 9-1 winners in a replay, having drawn the initial tie 1-1 two days previously.
We say: Tranmere 0-3 Tottenham
Tranmere have struggled past a couple of teams well below them in the football pyramid so far in this competition, and there have not been any signs that they will be able to cope with Tottenham on Friday night. Even a second-string Spurs side should be strong enough to comfortably see off their hosts.