Type 2 diabetes is a complex and heterogeneous metabolic condition that has reached epidemic proportions, affecting more than 150 million individuals worldwide. Maintenance of near-normal glucose control in patients with type 2 diabetes been shown to be associated with a reduced risk of microvascular complications as well as a trend toward reduction of macrovascular events. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary to restore acceptable glycemic control for many patients. The molecular reasons for the different responses to antidiabetic therapy are not clear, and the possibility that genetic factors may predispose to failure to respond adequately to oral antidiabetic agents remains an open question. Pharmacogenetics is an emerging discipline that involves the search for genetic polymorphisms, commonly observed among the general population, which influence drug response. Interesting candidate genes belong to three main groups: 1) genes encoding for drug metabolizing enzymes and/or transporters that influence pharmacokinetics; 2) genes encoding for targets and/or receptors of drugs that influence pharmacodynamics; and 3) genes encoding for proteins that are involved in the causal pathway of disease and are able to modify the effects of drugs. In this review, we will discuss our current understanding of genetic polymorphisms that may affect responses of patients with type 2 diabetes to antidiabetic oral treatment as well as the main challenges, which should be addressed in order to translate pharmacogenetics principles into widespread clinical practice.