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Diane Lane took the part because she wanted to do something different from her recent roles and wanted to keep the shoot local. She was extremely nervous about any improv that Cusack added to the film. When Cusack tried to make her improv she thought, "I don’t feel that confidence. I start blushing profusely and I get all sweaty and, I don’t know. Old school." John Cusack was about to do another film in Europe but it fell through at the last minute. He met with Goldberg and after reading the script they asked him to be in the film. Impressed with the actors that were already signed on, Cusack thought, "that's a pretty great pedigree, so I was kind of happy to be asked to join such a great group." Cusack had always wanted to work with Lane and had been following her career for some time. Kyra Sedgwick was originally cast in the part of Carol Nolan, which was ultimately played by Elizabeth Perkins. Brad William Henke took the role of Leo because he "fell in love with the fact that it wasn’t a stereotypical character." The crew did not mind what the character looked like and he was able to play a normal guy.

Goldberg was first interested in starting this project when he found Cook's book. He thought it had a lot of humor and started working on getting the film rights. Goldberg worked closely with Cook, sharing all the draft copies with her and asking for input. He even included her in the casting process. Even though Cook only made it on set twice she was "so pleased with what they’ve done. It's really such a tribute to the book and just a great movie in its own right." Goldberg's "process is to just get an actor and then write and re-write and work on the set." Goldberg was constantly bringing new pages to the set while Cusack contributed ideas for him to work with. Cusack also performed in takes where Goldberg allowed him to say whatever came out of his mouth.

Goldberg chose a Newfoundland to play the part, even though it was a different breed in the novel. Mother Teresa was played by two females, Molly and Mabel. Lane explained, "Like with kids, they prefer hiring twins." The dogs were chosen when they were only puppies and were trained by Boone Narr for several months before filming. During filming the dogs were still puppies, being 6 months old and 80 pounds. When production ended Goldberg adopted both dogs. Part of the training of the dogs was to follow the commands of the trainer who was situated off-camera while focusing attention on the actor.

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