The 49ers enter the week leading the league in sacks allowed with 19, so the Patriots are hoping their pass rush can produce some big numbers Sunday in San Francisco.
The target of their venom will be former Patriots' practice squad quarterback J.T. O'Sullivan, who spent parts of 2006 in New England.
"Hopefully, we'll be reacquainted," defensive end Richard Seymourtold the Boston Globe.
The danger in that is allowing the big play if the defenders can't get to the quarterback in time.
"Sometimes you get to [the quarterback] before he gets it off, but a lot of times you don't and they hit a lot of 20-, 25-, 30-yard completions," head coach Bill Belichicktold the Providence Journal.
Some of the players barely remember O'Sullivan's brief stint in New England, but they know they need to stop him.
"Somebody saw some potential in him and he's doing good," safety Rodney Harrisontold the MetroWest Daily News.
The Patriots also need to contain San Francisco's running game, which is led by Frank Gore.
"We understand defensively, if we're going to be good in this league, we have to be able to stop the run first," Seymour told the Boston Herald.
Another goal defensively is to get off the field on third down.
"Third down is the money down," Seymour told the Quincy Patriot Ledger.
The field position battle will also be an important. The edge goes to New England, which leads the league in kick return yards entering Week 5.
"We work at it hard, like we do everything else," fullback Heath Evanstold the Worcester Telegram & Gazette.
49ers tight end Vernon Davis apologized for lashing out at his teammates during Sunday's loss to New Orleans because he caught only one pass.
"It was just me being me," Davis told the San Jose Mercury News.
O'Sullivan, meanwhile, is looking for ways to avoid contact against the Patriots.
"We need to execute better," guard Tony Wraggletold the San Francisco Chronicle.