Thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel diseases and other immune regulation disorders. Active metabolites of thiopurines act as purine antagonists and inhibit endogenous protein synthesis, synthesis of DNA, RNA and some coenzymes. Thiopurine drugs have a relatively narrow therapeutic index and it is very important to understand their metabolism in the body as well as the wide interindividual variability. Almost one third of patients do not respond to thiopurines, and 20-25% of patients who start taking them develop some form of side effects. One of the important risk factor that may lead to toxicity, most often myelosuppression, is the genetic polymorphism of the enzymes which are involved in the metabolism of the thiopurines such as thiopurine methyltransferase (TPMT), xanthine oxidase (XO) and inosine triphosphatase pyrophosphatase (ITPA). Pretreatment determination of thiopurine methyltransferase (TPMT) status to optimize dosage before commencing thiopurine therapy is now a routine in many countries. Toxicities and adverse events resulting from drug-drug interactions should also be taken into account with thiopurine drugs.