Both considered significant underdogs in a group which also contains Napoli and holders Liverpool, these two sides will be looking to prove that they are not here to simply make up the numbers in the competition.
Tuesday night has been a long time coming for Salzburg, who are appearing in the Champions League groups for only the second time and the first since 1994-95.
A lot has happened at the club since then; a controversial rebranding following Red Bull's 2005 purchase of the club saw them lose some fans, while they have been thwarted in qualifying for this competition on no fewer than 13 occasions - including seven in a row before this season, despite not actually having lost a qualifying match inside normal time since 2015.
Salzburg will no doubt have been delighted to learn that last season's domestic title - their sixth in a row - guaranteed them a direct passage into the group stages this time, then, having been forced to settle for Europa League football up to this stage.
Last season's European campaign may provide some hope that they can upset the odds, though, having won all six of their group games for a competition-record third time before beating Napoli in the home leg of their last-16 clash.
A heavier defeat in the first leg against a team they have again been paired with in Group E meant that they crashed out on aggregate, but beating the likes of Napoli, RB Leipzig - who are also in the Champions League this season - and Celtic will no doubt help them to believe that they belong at this level.
The hosts certainly come into this match in fine fettle; they have won all seven of their matches across all competitions so far this season, scoring 34 goals in the process including seven in their most recent outing.
Of course, the quality of opposition must be taken into account, but there is no doubting that Salzburg are one of the form teams in Europe and Genk will go into this match as underdogs in what is their first Champions League showing since 2011-12 and only their third ever.
A fourth Belgian title last season sealed their place in the group stages automatically - the first time they have not had to go through the qualifiers - although they are yet to actually win a game in the competition proper.
Indeed, their last two away Champions League outings have seen them ship 12 goals without reply, while they have only ever won one including qualifiers whereas Salzburg are unbeaten in their last 18 European home games.
Matters look just as bleak on the domestic front too, with Friday's defeat at Sporting Charleroi already the defending champions' third of the league season to leave them ninth in the 16-team table with 10 points from seven games - seven fewer than they had at the same stage of last term.
The Belgian outfit's scoring record on the continent does give them a glimmer of hope, having netted in 29 of their last 30 such outings, although those have all come in the Europa League.
Red Bull Salzburg form: WWWWWW
Genk form: LLWWDL
In 19-year-old Erling Haaland Salzburg have arguably Europe's most in-form player, and he continued that at the weekend with another hat-trick - incredibly his third of the season already.
The Leeds-born son of former Manchester City defender Alf-Inge Haaland has 14 goals in eight appearances across all competitions this season and will now be looking to prove himself on the big stage with Europe's finest clubs beginning to circle - if they weren't already after his nine-goal haul in an Under-20 international for Norway in May.
There are plenty of other attacking threats should the teenager, who was rewarded with his first senior international cap during the recent break, find things more difficult in the Champions League, with Masaya Okugawa, Hwang Hee-Chan, Sekou Koita, Patson Daka and Takumi Minamino all boasting impressive goal-to-game ratios this season too.
The Belgians have had to cope with the loss of Leandro Trossard, who joined Brighton & Hove Albion during the summer, and so far Ally Mbwana Samatta has helped to fill the void with five goals in six league matches - a return which puts him joint-top of the scoring charts despite Genk's indifferent start to the campaign.
Samatta is a notable doubt for the visitors due to a knee injury, though, while Neto Borges could also miss out with a foot issue.
Salzburg possible starting lineup:
Stankovic; Kristensen, Ramalho, Wober, Ulmer; Minamino, Junuzovic, Bernede, Szoboszlai; Hwang, Haaland
Genk possible starting lineup:
Coucke; Uronen, Dewaest, Cuesta, De Norre; Hrosovsky, Berge, Heynen; Paintsil, Onuachu, Ndongala
We say: Salzburg 3-0 Genk
The form book, the home and away records and pretty much everything else points to a comfortable home win in this match. Salzburg score a lot of goals and, considering Genk could be without their own main marksman, we are backing them to send out a statement to Liverpool and Napoli that they are in with a shout of challenging for the knockout rounds.