Justin Kirk and Crystal the monkey Justin Kirk and Crystal the monkey

There are a lot of actors in Hollywood who would refuse to play second banana to a monkey.

Animal Practice star Justin Kirk, on the other hand, is more than happy to share the spotlight.

"The thing about Crystal [the capuchin monkey who plays "Dr." Rizzo] is, all of the attention that comes to her she deserves and more. She is one of a kind and a national treasure," Kirk tells TVGuide.com. "Truth be told, I miss her if I haven't had a scene with her for a while."

Being comfortable with animals is almost a prerequisite for those working on Animal Practice, premiering Wednesday at 8/7c on NBC. Kirk stars in the half-hour comedy as a misanthropic veterinarian who cares deeply for his four-legged patients, but can't stand their owners.

Get the scoop on Animal Practice and all the must-see new fall shows

Although Kirk admits he has no pets at home — "I don't even have any plants" — he thought a comedy centered on an animal hospital had potential. "It was a setting that seemed to be strangely untapped in the world of television comedy," Kirk says of his decision to sign on. "I was doing a play and we had another season of Weeds to shoot. [NBC Entertainment Chairman] Bob Greenblatt e-mailed me and said, 'It looks like you guys are going to be winding up over there and we would love you to take a look at this.'"

A network sitcom about lions and tigers and bears (oh my!) is worlds away from Kirk's eight-year gig on the profanity-, nudity- and drug-laden Showtime comedy. According to Kirk, that's exactly what the doctor ordered. "I would never have wanted to do another 'edgy' — for the lack of a better word — cable show because Weeds is sacred to me," Kirk says. "I wanted my next thing to be something far from it and this is, but it's also totally fulfilling to me as an actor in different ways."

First Look Video: Meet Animal Practice's "demanding" star — Crystal the Monkey!

However, Animal Practice isn't just about the animals, contrary to popular belief. In addition to trading in pot for pups, Kirk gets a new will-they-or-won't-they love interest in the form of JoAnna Garcia Swisher. The Reba actress plays Dorothy, George's ex-girlfriend-turned-boss. After leaving him three years earlier, Dorothy inherits the animal hospital he works at from her grandmother, and she makes it known that she plans to keep a close eye on George, Dr. Rizzo and the rest of the staff. "My biggest hope was to approach this with passion," Garcia Swisher says. "I wanted Dorothy to not be there because she had to be. I wanted Dorothy to be there because she wanted to be and because she loved her grandmother that much that she knew how much this hospital meant to her and that she wanted to do right by her legacy."

Garcia Swisher replaces Amy Huberman, who played Dorothy in the original pilot. "I really appreciated the fact that I was able to create this character in a certain way and bring my voice to her," she says. "My character is not engaged anymore. She's a single gal coming in and we were able to really play with those emotions."

Animal Practice's monkey business overshadows human business

Will those emotions lead to something more than a boss-employee relationship between the two? "Justin and I have an extreme chemistry that is rare," she says. "It's kind of undeniable. I think at one point we're going to have to really address it. In the meantime, I really hope this turnstile of hot guys come in — try to get my husband [New York Yankee Nick Swisher] a little jealous."

Kirk says that chemistry stretches to the entire cast — which ranges from sitcom vets (Garcia Swisher, Reaper's Tyler Labine) to comedy club grads (MADtv's Bobby Lee and UCB-er Betsy Sodaro). "The ensemble never ceases to delight and amaze me," he says. "I think we have a really crack team of comic actors who all have really wildly varying styles of performance but it jells and we all come together."

Adds Garcia Swisher: "It's got the best of both worlds. The show is really about the people and their relationships. ...The animals are a cherry on top of the show. "

Animal Practice premieres on Wednesday, Sept. 26 at 8/7c on NBC.