The study of genetic determinants underlying drug outcome is rapidly advancing. Initial success was realized within the context of candidate pharmacokinetic genes and serious adverse drug reactions, particularly for drugs with narrow therapeutic indices. Although genetic predictors of outcome have proven useful in other contexts, effect size has typically been small. To address these challenges, the clinical and scientific communities have begun studying larger numbers of gene variants (often at the genome-wide level) in cohorts of increasing sample size. Electronic health records are being increasingly used for this purpose. Longitudinal data available in practice-based datasets will position investigators to characterize genetic factors with small but reproducible effects on drug outcome in the context of gene-environment interactions.