In this perspective, we present the idea that SRC family coactivators are likely agents in human polygenic disease states based upon a number of interlocking aspects of their biology. We argue that their role as key integrators of environmental signals and their ability to regulate the expression of myriad downstream genes makes them likely candidates for strong positive evolutionary selection pressures. Based on the fact that they work as part of multiprotein coactivator complexes, we predict that individual coactivator alleles exist as weakly penetrant disease alleles, each contributing only a fraction of transcriptional activity to the whole coactivator complex. In this way, individual coactivator alleles are free to evolve in the absence of strong negative selection. Emerging genomic and proteomic approaches promise to advance the characterization of coactivator proteins and their physiological functions, allowing us to have a greater appreciation of their roles as master regulators at the nexus between genetics, reproduction, metabolism, cancer, other human diseases, and our environment.