The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. This is likely to be mediated by increasing polypharmacy, which increases the likelihood for drug-drug interactions. Tools utilized by healthcare practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To date there have been limited published studies on impact of genetic variation on drug-drug interactions. In this review, we establish a detailed classification for pharmacokinetic drug-drug-gene interactions, and give examples from the literature that support this approach. The increasing availability of real-world drug outcome data linked to genetic bioresources is likely to enable the discovery of previously unrecognized, clinically important drug-drug-gene interactions.