The Red Devils are ranked number one in the world, but they have famously failed to beat Group E opponents Wales in recent encounters.
The highest profile of those recent meetings between these sides came at the quarter-final stage of Euro 2016, a game which Wales won 3-1 to stun the watching world.
Wales had also defeated Belgium on home soil in the qualifying campaign, while also holding them to a goalless draw in the reverse fixture in Brussels.
Indeed, the Dragons are unbeaten in four against Belgium and enter this latest tussle in good shape - on the field at least - after going 11 competitive games without defeat.
After qualifying for this summer's rescheduled Euro 2020, Wales followed that up with an unbeaten Nations League campaign that earned them promotion to the top tier of groups.
The Dragons have been without boss Ryan Giggs for their last few games, and will be for at least their next three, as he remains under investigation due to an assault allegation.
Rob Page stepped up in November and guided his side to wins over Republic of Ireland and Finland, following on from a goalless friendly draw with the United States.
This showdown with Belgium is the toughest of tests, however, with the Red Devils ranked the number one country in the world.
That is down to their incredible consistency, losing just three of their last 50 matches, the most recent of those losses coming against England in October.
The ultimate aim for Belgium will be to win the Euros, though the longer-term target is to not only reach Qatar 2022 but also win the competition.
A golden age of Belgian football is thriving and Roberto Martinez will be desperate to keep the feel-good factor alive, but the Red Devils know nothing can be taken for granted against Wales.
Belgium thought they were going to be without leading goalscorer Romelu Lukaku for this match following a coronavirus outbreak at Inter Milan, but he joined up with his teammates on Monday and should therefore be available to start.
As for Wales, they will once again be without Aaron Ramsey because of an injury sustained with club side Juventus last week.
The Dragons have picked up wins in Ramsey's absence in the recent past, though, and Page also now has the bonus of Joe Allen's return to the squad for the first time since 2019.
Wayne Hennessey picked up an injury for Wales in October that kept him out of action until last month, but he has proved his fitness for Crystal Palace Under-23s and should therefore be okay to start on Wednesday.
Belgium possible starting lineup:
Courtois; Alderweireld, Denayer, Vertonghen; Chadli, Dendoncker, Tielemans, Hazard; Mertens, De Bruyne; Lukaku
Wales possible starting lineup:
Hennessey; Mepham, Rodon, Ampadu; Roberts, Allen, Morrell, Norrington-Davies; Bale, Moore, James
We say: Belgium 2-1 Wales
Wales have a great recent record against Belgium and enter this game unbeaten in 11 competitive matches since June 2019.
However, the Red Devils will be eager to get their latest qualifying campaign off to a winning start and, blessed with the options Martinez has available, we can see them coming out on top on Wednesday.
Our analysis of all available data, including recent performances and player stats up until an hour before kickoff, suggested the most likely outcome of this match was a Belgium win with a probability of 62.82%. A draw had a probability of 22% and a win for Wales had a probability of 15.16%.
The most likely scoreline for a Belgium win was 1-0 with a probability of 13.37%. The next most likely scorelines for that outcome were 2-0 (12.36%) and 2-1 (9.61%). The likeliest drawn scoreline was 1-1 (10.39%), while for a Wales win it was 0-1 (5.62%). The actual scoreline of 3-1 was predicted with a 5.9% likelihood. Our data analysis correctly predicted that Belgium would win this match.