AbstractThe goal of this unit is to introduce epistasis, or gene‐gene interactions, as a significant contributor to the genetic architecture of complex traits, including disease susceptibility. This unit begins with an historical overview of the concept of epistasis and the challenges inherent in the identification of potential gene‐gene interactions. Then, it reviews statistical and machine learning methods for discovering epistasis in the context of genetic studies of quantitative and categorical traits. This unit concludes with a discussion of meta‐analysis, replication, and other topics of active research. © 2017 by John Wiley & Sons, Inc.