Directed evolution has emerged as an important tool for engineering proteins with improved or novel properties. Because of their inherent reliance on randomness, directed evolution protocols are amenable to probabilistic modeling and analysis. This chapter summarizes and reviews in a nonmathematical way some of the probabilistic works related to directed evolution, with particular focus on three of the most widely used methods: saturation mutagenesis, error-prone PCR, and in vitro recombination. The ultimate aim is to provide the reader with practical information to guide the planning and design of directed evolution studies. Importantly, the applications and locations of freely available computational resources to assist with this process are described in detail.