Early genome-wide association studies (GWAS) using relatively small samples have identified both rare and common genetic variants with large impact on severe adverse drug reactions, dosing, and efficacy. Here we outline the challenges and recent successes of the GWAS approach in disease genetics and the ways in which these can be applied to pharmacogenomics for biological discovery, determination of heritability, and personalized treatment. We highlight that the genetic architecture of drug efficacy reflects a complex trait yet that of adverse drug reactions more closely mirrors the architecture of Mendelian diseases and how this difference affects future study design. Given that multiple layers of biological data are increasingly available on large samples from biorepositories linked to electronic medical records, GWAS will remain a key component of the systems biology approach to uncovering small to moderate genetic determinants of drug response; these discoveries should move us closer to a personalized approach to health care.