For dos Santos, the fight represents an opportunity to redeem himself after losing the heavyweight title to Velasquez last year, just 13 months after defeating the American in Anaheim.
But Velasquez's win over JDS suggested that the Brazilian's win could have been a fluke, as dos Santos appeared unable to come up with a sufficient defense for Velasquez's relentless attack at UFC 155.
Heading into tonight's title fight, here's a look at the keys to victory for both dos Santos and Velasquez.
Junior dos Santos
Landing an early knockout
For the 29-year-old dos Santos, whether or not he's able to land heavy shots on Velasquez, particularly during the early stages of the match, may be the deciding factor in who leaves Houston with the title.
Obviously, dos Santos needs to maintain his composure defensively, because as we saw during the pair's second fight, weathering Velasquez's combinations, takedowns and accuracy is of the utmost importance for JDS.
During their first meeting, dos Santos managed to come away with a victory by getting after the champion early, and though he may have been helped in part by Velasquez's shoulder injury, his furious early attack got him the victory.
His overhand right was the decisive blow just over a minute into the fight, and for dos Santos to take the third installment of the trilogy, it may take a similar effort this time around.
The knockout punch wasn't there during their second fight, and we saw what happened. So for JDS to win, he's got to be opportunistic when his chances to land big shots arise.
If this one goes the distance, Velasquez has to be the favorite, but JDS' advantage in power could allow him to land a knockout during the early stages of the tilt.
Wear dos Santos down with tireless offense
Last year, Velasquez earned his title back by furiously attacking dos Santos from start to finish, and he'll aim to do the same in Houston tonight.
During their last clash, Velasquez's effort offensively was masterful, as the champion became the first UFC fighter to reach triple-digits in significant strikes landed (111) and double-digits in takedowns (11), which obliterated the previous record of 81 and 11, respectively.
In order to defend his title against the younger Brazilian, Velasquez will have to break his opponent's defense down in similar fashion, while also being aware of dos Santos' power, which is what proved to be the difference in their first meeting.
These two fighters know one another very well now, so dos Santos will undoubtedly be more aware of Velasquez's desire to get things done on the ground. He'll likely have to land a sufficient number of strikes in order to win.
He's very solid defensively against takedowns, and given how things turned out last time, look for Velasquez to try and establish control over dos Santos with early takedowns.