Genetic variation can impact on efficacy and risk of adverse events to commonly used oral agents in diabetes. Metformin is not metabolized and its mechanism of action remains debated; however, several cation transporters have been identified. Variation in these pharmacokinetic genes might influence metformin response. Conversely, although the cytochrome P450 system has been implicated in sulfonylurea response in some small studies, to date variants affecting pharmacodynamics, including those in ABCC8 (SUR1) and TCF7L2, are the most promising. For thiazolidinedione response, variants in PPARG or ADIPOQ (adiponectin) have been variably associated with response. With increasing well-phenotyped cohorts and new methods, including genome-wide association studies, the next few years offer great hope to use pharmacogenetics to unravel drug and disease mechanisms, as well as the possibility to individualize therapy by genotype.