Probably all heritable traits, including disease susceptibility, are affected by interactions between mutations in multiple genes. We understand little, however, about how genes interact to produce phenotypes, and there is little power to detect interactions between genes in human population studies. An alternative approach towards understanding how mutations combine to produce phenotypes is to construct systematic genetic interaction networks in model organisms. Here I describe the methods that are being used to map genetic interactions in yeast and C. elegans, and the insights that these networks provide for human disease. I also discuss the mechanistic interpretation of genetic interaction networks, how genetic interactions can be used to understand gene function, and methods that have been developed to predict genetic interactions on a genome-wide scale.