Considerable interindividual variabilities in clinical efficacy and adverse events are sometimes recognized in the treatment of Type 2 diabetes mellitus with oral antihyperglycemic drugs. Metformin is the most commonly used biguanide in clinical practice, and also improves insulin resistance and reduces cardiovascular risk. However, certain patients taking metformin do not respond sufficiently. The molecular reasons for the variability in response to metformin are not clear. However, it has been recently suggested that genetic factors may be responsible for the variability. Metformin is not metabolized but is transported by at least two organic cation transporters (OCT), OCT1 and OCT2. Recently, genetic polymorphisms in OCT 1 and OCT2 have been found to be associated with changes in pharmacokinetic/pharmacodynamic responses to substrate drugs. This review focuses on the impact of the genetic polymorphism of organic cation transporters on transport activity, and the implications for the clinical efficacy of metformin.