In 2012 Pyle starred as Sue on the TV series Greetings from Home. From 2013 to 2014 she starred as Eileen in the television series Cleaners. In 2014 she also starred as Dina in the series Jennifer Falls. Missi has starred in the movies As Good as it Gets, Galaxy Quest, Josie and the Pussycats, Let It Snow, Home Alone 4, Bringing Down the House, Big Fish, Along Came Polly, 50 First Dates, Soul Plane, DodgeBall: A True Underdog Story, Anchorman: The Legend of Run Burgundy, Charlie and the Chocolate Factory, Harold & Kumar Escape from Guantanamo Bay, The Art, Percy Jackson: Sea of Monsters, A Haunted House 2, and Gone Girl. Pyle was nominated and MTV Movie Award for Best Fight in 2004. She is one half of the country-rock band Smith & Pyle with actress Shawnee Smith.