That's exactly whom he faces on Wednesday as the Angels' starter looks to turn around his early-season struggles when he pitches against Oakland's Bartolo Colon.
In 23 career outings against the A's, Santana has set personal bests with 13 wins and a 2.00 ERA (minimum two starts). But something will have to change from his first two outings, as Santana noted he is "mad at the way I've started," with an 0-2 record and a 7.71 ERA.
"I just have to go out and have better location with my pitches," Santana said. "I need to have my fastball hitting the corners. That's the key."
A day after the A's snapped a three-game skid with a come-from-behind win in Anaheim on Tuesday, they feel just as good about their own guy on the mound. The righty Colon is 8-5 with a 3.69 ERA in 18 career starts against his former team and, most recently, pitched seven shutout innings against the Mariners with ease.
Colon's calm demeanor has had a soothing effect of sorts on a young A's team.
"Not only does it serve him well, but it serves us well because we feel calm behind him," manager Bob Melvin said. "If you have someone out there that's pacing around and nervous and fidgety and so forth, the rest of the team feels it. And he's anything but. He's pitching like he's pitching on the back field in a [Spring Training 'B'] game, and our guys feel pretty calm behind him."
For the struggling Angels, who fell to 4-7 with a loss on Tuesday, there has been some good news. A couple pivotal pieces to their lineup -- Torii Hunter and Kendrys Morales -- appear to have broken out of their respective slumps.
Morales has five hits and four RBIs in his last two games, while Hunter has four hits during that time.
A's: Carignan, Cowgill sent down in pair of roster moves
To make room for No. 5 starter Tyson Ross, the A's optioned outfielder Collin Cowgill to Triple-A Sacramento before Tuesday's game.
"That was a difficult one," Melvin said. "The fact is we had six outfielders here and I just wasn't able to get Collin as many reps as I would like. When you tell a guy like that he's going down, I really have no reason to tell him he's going down, because he did everything we asked. It was just a numbers game."
Cowgill had appeared in only three contests drawing three walks in seven plate appearances, but no hits.
The A's also optioned struggling reliever Andrew Carignan, who was replaced by righty Neil Wagner. In 5 1/3 innings with the River Cats, Wagner posted a 5.06 ERA, striking out eight and walking none.
Oakland has been shut out three times this season, which is the most in baseball, and its 33 runs scored are the fewest among American League clubs.
Angels: Living and dying with the starters
Angels manager Mike Scioscia has been saying the Halos will turn their poor record around as soon as the starting pitching does.
The stats back him up. In the Angels' four wins this season, the starters have posted a 0.65 ERA, compared with a 6.99 mark in their seven losses.
Tuesday's loss was the only real anomaly, as starter Dan Haren worked 6 2/3 innings of one-run ball only to have the bullpen blow the lead.
Albert Pujols is still homer-less this season through 45 at-bats, though he is riding a seven-game hitting streak that has raised his average to .267. The 11 straight games he has gone without a long ball is Pujols' longest stretch to start a season.
Angels closer Jordan Walden still has not entered a game in a save situation this season. He hasn't allowed a run or a hit in two innings, while striking out three.
The Angels are 12-6 in their past 18 games against Oakland at Angel Stadium. In those 12 victories, they have posted a team ERA of 1.96.
A's second baseman Jemile Weeks is hitting .326 against the Angels in his career. He has a homer and eight RBIs in 46 at-bats.