The epidemiologic approach enables the systematic evaluation of potential improvements in the safety and efficacy of drug treatment which might result from targeting treatment on the basis of genomic information. The main epidemiologic designs are the randomized control trial, the cohort study, and the case-control study, and derivatives of these proposed for investigating gene-environment interactions. However, no one design is ideal for every situation, and methodological issues, notably selection bias, information bias, confounding and chance, all play a part in determining which study design is best for a given situation. There is also a need to employ a range of different designs to establish a portfolio of evidence about specific gene-drug interactions.In view of the complexity of gene-drug interactions, pooling of data across studies is likely to be needed in order to have adequate statistical power to test hypotheses. We suggest that there may be opportunities (i) to exploit samples from trials already completed to investigate possible gene-drug interactions; (ii) to consider the use of the case-only design nested within randomized controlled trials as a possible means of reducing genotyping costs when dichotomous outcomes are being investigated; and (iii) to make use of population-based disease registries that can be linked with tissue samples, treatment information and death records, to investigate gene-treatment interactions in survival.