The pharmacological interventions currently available to control type 2 diabetes mellitus(T2DM) show a wide interindividual variability in drug response, emphasizing the importance of a personalized, more effective medical treatment for each individual patient. In this context, a growing interest has emerged in recent years and has focused on pharmacogenetics, a discipline aimed at understanding the variability in patients’ drug response, making it possible to predict which drug is best for each patient and at what doses. Recent pharmacological and clinical evidences indicate that genetic polymorphisms(or genetic variations) of certain genes can adversely affect drug response and therapeutic efficacy of oral hypoglycemic agents in patients with T2 DM, through pharmacokinetic- and/or pharmacodynamic-based mechanisms that may reduce the therapeutic effects or increase toxicity. For example, genetic variants in genes encoding enzymes of the cytochrome P-450 superfamily, or proteins of the ATP-sensitive potassium channel on the beta-cell of the pancreas, are responsible for the interindividual variability of drug response to sulfonylureas in patients with T2 DM. Instead, genetic variants in the genes that encode for the organic cation transporters of metformin have been related to changes in both pharmacodynamic and pharmacokinetic responses to metformin in metformin-treated patients. Thus, based on the individual’s genotype, the possibility, in these subjects, of a personalized therapy constitutes the main goal of pharmacogenetics, directly leading to the development of the right medicine for the right patient. Undoubtedly, this represents an integral part of the translational medicine network. The pharmacological interventions currently available to control type 2 diabetes mellitus (T2DM) show a wide interindividual variability in drug response, emphasizing the importance of a personalized, more effective medical treatment for each individual patient. In this context, a growing interest has emerged in recent years and has focused on pharmacogenetics, a discipline aimed at understanding the variability in patients’ drug response, making it possible to predict which drug is best for each patient and at what doses. Recent pharmacological and clinical evidences that the genetic polymorphisms (or genetic variations ) of certain genes can adversely affect drug response and therapeutic efficacy of oral hypoglycemic agents in patients with T2 DM, through pharmacokinetic- and / or pharmacodynamic-based mechanisms that may reduce the therapeutic effects or increase toxicity. For example, genetic variants in genes encoding enzymes of the cytochrome P-450 superfamily, or proteins of the ATP-sensitive potassium channel on the beta-cell of the pancreas, are responsible for the interindividual variability of drug response to sulfonylureas in patients with T2 DM. Instead, genetic variants in the genes that encode for the organic cation transporters of metformin have been related Thus, based on the individual’s genotype, the possibility, in these subjects, of a personalized therapy constituted the main goal of pharmacogenetics, directly leading to the development of the right medicine for the right patient. Undoubtedly, this represents an integral part of the translational medicine network.