Although it falls on just the second weekend of a five-round tournament, it is a Test match that could see the Aviva Stadium victors establish irresistible title momentum.
Wales are chasing an unprecedented Six Nations title hat-trick, while Ireland continue to make impressive progress under new coach Joe Schmidt.
Wales boss Gatland has made three changes from the side that beat Italy 23-15 last weekend, with captain Sam Warburton, prop Gethin Jenkins and lock Andrew Coombs all handed starts.
Warburton, who began his comeback from a shoulder injury off the bench three days ago, replaces openside flanker Justin Tipuric, while 101 times-capped Jenkins takes over from Paul James and Coombs is in for lock Luke Charteris, who has a hamstring injury.
James and Tipuric are among the replacements, where there is also a spot for uncapped Scarlets lock Jake Ball.
Ball, 22, emigrated to Australia five years ago but his rugby progress Down Under was spotted by the Scarlets, and they signed him on a three-year deal in 2012.
The Berkshire-born forward qualifies for Wales through his father, who was born in Colwyn Bay.
"Gethin has trained well, and Sam comes back into the side as well. We know it is going to be pretty physical up front," Gatland said.
"In terms of people in the world stealing and poaching ball and winning penalties, Sam is definitely one of the best in world rugby.
"We will be looking forward to competing quite hard at the breakdown.
"It is a shame for Luke, and (centre) Jonathan (Davies) is still not quite right. He will probably train with us this week and maybe have another game for the Scarlets next week.
"Other than that, we are in a pretty healthy state."
While Gatland has made three switches up front, the back division is unchanged.
Full-back Leigh Halfpenny, who passed 350 Test points during the Italy match, will win his 50th cap, a landmark that James is also set to reach if he features off the bench.
Wales have won three of their last four games against Ireland, but Schmidt's team delivered a strong display to account for Scotland 28-6 in their Six Nations opener last Sunday.
"By all accounts, they (Ireland) have spent the last two weeks preparing for this game on Saturday," Gatland added.
"We are aware of that, and they are two teams that won their opening game going head to head. It is a massive game for both teams.
"We haven't lost an away match in the Six Nations since 2011, and we have to have the belief and confidence that we can do it again this weekend.
"We feel in most tournaments that we get stronger as it goes on, and that will need to be the case this weekend."
Warburton, meanwhile, will make his first start since Wales lost to Australia on November 30, having received a huge Millennium Stadium ovation when he appeared 16 minutes from time against Italy.
"I couldn't help but hear it when I ran on the pitch," he said.
"It was a great feeling, to be honest, to think that that many people were acknowledging and supporting you. It was one of the highlights of my career, it was quite overwhelming.
"I was really pleased to get back on the pitch and feel the speed and intensity of Test match rugby and just get rid of a few cobwebs.
"I have always found Ireland one of the more difficult sides to play against.
"The game is a bit more open, it is physical at the breakdown. It ticks all the boxes for a Test match.
"If I had to pick games that I really look forward to playing in, Ireland games are always there."
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- Gethin Jenkins
- Sam Warburton