The two meet in the biggest game of the domestic rugby league season at Old Trafford on Saturday, for the right to be crowned Super League champions.
"There's a healthy hatred there between the clubs," Wigan head coach Shaun Wane told BBC Sport. "I respect what St Helens are all about but my players are coming here really badly wanting to win."
St Helens head coach Nathan Brown added: "It's a Grand Final and it's against Wigan - two sides that have mutual respect, but bitter hatred for each other."
As well as the location of the two towns - around 10 miles separate their stadiums - their rivalry has been built on their success.
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It was not an exciting start to the meetings between the two. The first derby took place in 1895, but neither side managed to score in a 0-0 draw.
Since then, Wigan have gone on to win a total of 20 titles including Grand Finals, the most of any club, with Saints sitting second with 12.
In the Challenge Cup it is a similar story, as the Warriors are the most successful team having won the trophy 19 times, with St Helens (12) third on the list behind Leeds.
This year's two regular-season meetings saw a victory apiece, with wins for the away team on both occasions, while just one point separated the two after 27 games, as St Helens secured the League Leaders' Shield for a fifth time.
Rarely are their contests without incident. During four fixtures in 2012, four red cards were produced, including three during a 26-man brawl in their Magic Weekend meeting.
"It doesn't come any bigger," continued Wane, 50, a Wiganer who came through the youth system at his hometown club and played for them for 10 seasons.
"Playing St Helens in Super League is big, playing in the Grand Final is big - when you put them together it's a huge occasion.
"I want to win it more than I did last year. This game is special. They show and tell us how much they hate us, and that's the way it is.
"The game is the biggest game in rugby league. I've played in Leeds-Bradford derbies and this is the main one."
The match will be Brown's last in charge at Saints, after he announced he will return to Australia for family reasons following their win over Catalans in the semi-final.
"It's a big occasion, regardless if it's someone's first game or someone's last game," added the Australian, 41. "A lot of emotion goes into a Wigan-Saints game on a normal occasion, never mind a Grand Final at Old Trafford."
When it comes to sporting rivalries, few are as fierce as the one between St Helens and Wigan.