Studies on resistance gene function and evolution lie at the confluence of structural and molecular biology, genetics, and plant breeding. However, knowledge from these disparate fields has yet to be extensively integrated. This review draws on ideas and information from these different fields to elucidate the influences driving the evolution of different types of resistance genes in plants and the concurrent evolution of virulence in pathogens. It provides an overview of the factors shaping the evolution of recognition, signaling, and response genes in the context of emerging functional information along with a consideration of the new opportunities for durable resistance enabled by high-throughput DNA sequencing technologies.