Genetically distinct individuals frequently exhibit qualitative and quantitative differences in phenotypic plasticity. These heritable differences in plasticity impact many traits of human concern, while also providing a potential substrate for artificial and natural selection. The genetic underpinnings of this variation in plasticity are often complex, involving many loci that may interact not only with the environment but also with each other. Thus, determining the genetic architecture and molecular mechanisms that produce plasticity can be challenging. This chapter summarizes key concepts for thinking about the genetic basis of plasticity, while also reviewing methods that enable genetic dissection of plasticity and empirical insights that have been obtained from work employing these techniques. It concludes by emphasizing the need to go beyond simple genetic characterizations and explicate the molecular, genetic, and systems biology mechanisms underlying plasticity. These mechanisms, and the plasticity they regulate, have an important bearing on a number of fundamental areas of biology, including genetics, ecology, and evolution.