The Hornets have won seven of their last eight games to open up a seven-point gap on third place, while Luton are 13th after returning to winning ways last time out.
Promotion back to the top flight at the first time of asking was the aim for Watford this term and, with just five games left to navigate, they are on course to achieving that.
However, with games against Norwich City, Brentford and Swansea City still to play, any sort of slip up this weekend could open the door for one of Brentford or Swansea to pounce.
Xisco's side have not really showed any signs of collapsing, though, with a recent 1-1 draw at Middlesbrough the only time they have dropped points since February 27.
Indeed, going further back, the Hornets have won 11 of their last 13 games and are the most in-form side in the second tier, followed by league leaders Norwich.
Xisco has challenged his players to make up the eight-point gap on Norwich, but nailing down second place is the main priority right now.
Luton will attempt to make life as difficult as possible for their high-flying opponents as they look to make it back-to-back wins, having defeated Wycombe Wanderers 3-1 last week.
This game will have an extra edge to it, too, given that these sides do not like each other - a rivalry that is said to date back to their formations in the late 19th century.
It is not just bragging rights on the line, of course, with Luton after the three points that may lift them above Stoke City into the top half of the division.
Four of Town's remaining five games are at home, but they have a very mixed record at Kenilworth Road this season, winning seven, drawing six and losing six.
That gives Nathan Jones's side a return of 27 points from 19 home matches, compared to 29 points from 20 away games for Watford.
This will be the first league meeting between Luton and Watford at Kenilworth Road since January 2006 - a 2-1 win for the Hornets in the Championship.
The Hatters have not beaten Watford at home in the league since August 1993, and they were defeated 1-0 at Vicarage Road in September's reverse fixture.
It took a quartet of substitutions before Luton got going against Wycombe, with George Moncur scoring from the bench to put himself in contention for a starting spot here.
Moncur also assisted a goal for Kazenga LuaLua, who is pushing for a rare inclusion in the starting XI this weekend.
Midfielder Tom Cleverley is less likely to feature after suffering a couple of setbacks on his return from injury.
One man who is fit and firing is Ismaila Sarr, who has been directly involved in more Championship goals this season than any other Watford player (16 – 12 goals, four assists).
Luton Town possible starting lineup:
Sluga; Clark, Pearson, Bradley, Naismith; Tunnicliffe, Mpanzu, Clark; Cornick, Adebayo, LuaLua
Watford possible starting lineup:
Bachmann; Femenia, Troost-Ekong, Sierralta, Masina; Sanchez, Hughes, Zinckernagel; Sarr, Pedro, Sema
We say: Luton Town 1-2 Watford
Second-placed Watford may have a healthy gap on the chasing pack, but they have a tough run of fixtures to see out the campaign.
A trip to rivals Luton will be far from straightforward, but the Hatters' home form is not the best and we can see Xisco's men getting the job done here.
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