Both clubs have already caused huge upsets in this year's competition, with RWE beating Bayer Leverkusen and Holstein Kiel overcoming Bayern Munich.
RWE actually lifted the DFB-Pokal in 1953, following that up by winning the German top tier in 1955 to qualify for the first ever rendition of the European Cup the following season, losing to Scottish side Hibernian in the first knockout round.
However, the Ruhr-based side have not competed in the Bundesliga since being relegated in 1977, and have been languishing in the fourth and fifth tiers of German football since 2008.
Christian Neidhart's side look to have a good chance of returning to the third tier, though, given that they currently occupy second place behind Borussia Dortmund's reserve team in the Regionalliga West.
The real excitement of RWE's season, though, has been in the DFB-Pokal. Having beaten Arminia Bielefeld, Fortuna Dusseldorf and Leverkusen on their way to the quarter-final, there is little doubt that the magic of the cup appears be on their side and they will have every confidence of beating Holstein Kiel on Wednesday.
RWE will not find it easy against their forthcoming opponents, though, with the visitors enjoying one of their finest ever seasons.
Holstein Kiel did win the German Championship in 1912, but unlike RWE, they have never competed in the Bundesliga.
Ole Werner looks to have every chance of ending that barren run, however, with his side currently second to VfL Bochum on goal difference in the second tier of German football.
Should Werner guide his side to their first ever cup semi-final, alongside gaining promotion to the Bundesliga for the first time in the modern era, the 32-year-old would clearly be considered a permanent club legend. While RWE have shown how dangerous they can be against Bundesliga opponents, Werner could not have wished for a better chance of doing so.
Rot-Weiss Essen DFB-Pokal form: WWW
Rot-Weiss Essen form (all competitions): WWDWWL
Holstein Kiel DFB-Pokal form: WWW
Holstein Kiel form (all competitions): WWWWLW
Top goalscorer Simon Engelmann will be determined to continue his phenomenal run in the cup, having scored in each of the previous three rounds so far.
Their hopes will largely hinge on the performance of Fin Bartels, with the 34-year-old enjoying a brilliant season since joining from Werder Bremen.
Rot-Weiss Essen possible starting lineup:
Davari; Hildebrandt, Heber, Hahn, Herzenbruch, Grund; Backszat, Grote, Kehl-Gomez; Young, Engelmann
Holstein Kiel possible starting lineup:
Gelios; Dehm, Lorenz, Wahl, Kirkeskov; Bartels, Lee, Meffert, Bieler, Reese; Serra
We say: Rot-Weiss Essen 1-1 Holstein Kiel
We can envisage a close encounter between these two non-Bundesliga sides, with plenty of nerves likely to be on display given the amount at stake.
There does feel something a little magical surrounding RWE in this competition this year, with Engelmann likely to get on the scoresheet once again, so we will back them to win after a penalty shoot-out.