Many phenotypes exhibit a plastic response to variation in environmental conditions, and genetic variation in this plastic response provides the opportunity for selection to act on plasticity itself. Although genetic variation in plasticity is well documented in many taxa, the genes that regulate plasticity are largely unknown. In this study, we investigated the genetic basis of natural variation in the plastic response of age-specific fecundity and lifespan to changes in dietary protein content using the Drosophila melanogaster Genetic Reference Panel. Variation in the plastic response of fecundity to diet was associated with 491 polymorphisms and 292 genes, and variation in the plastic response of lifespan to diet was associated with 29 polymorphisms and 15 genes. We used our data to test predictions of two hypotheses on the genetic mechanisms of plasticity, the allelic sensitivity hypothesis (the plastic response of traits is regulated by the genes that affect the trait means) and the gene regulation hypothesis (plasticity is regulated by genes that are independent of those contributing to trait variation). We found evidence to support both mechanisms; however, our data suggest that the gene regulation mechanism is the more common mechanism. This decoupling of trait genes from those regulating their plastic response reduces the potential constraints of pleiotropy, facilitating adaptive independent evolution of the trait means and their plastic response to environmental variation.