The thiopurine drugs, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used in the treatment of acute leukaemias. A derivative of 6-MP, azathioprine, and 6-MP itself are used as immunosuppressants, in the treatment of inflammatory bowel disease, autoimmune conditions and following transplantation. The thiopurines are pro-drugs and need to be metabolised to exert their cytotoxic effects. One prominent cytotoxic action of these drugs is their incorporation into DNA and RNA after conversion to thioguanine nucleotides (TGNs). Competing with TGN formation is methylation of the pro-drugs and their metabolites by thiopurine methyltransferase (TPMT). This enzyme exhibits wide inter-individual variation in activity, which appears to be due, at least partly, to the presence of single nucleotide polymorphisms (SNPs). Variation in TPMT activity has an effect on the metabolism and cytotoxicity of the thiopurine drugs. Levels of TGN production, during treatment with the thiopurine drugs, have been shown to be inversely related to TPMT activity. Low TPMT activity has been associated with profound and life-threatening myelosuppression, whereas high TPMT levels have been associated with decreased efficacy in treatment with 6-MP or azathioprine. There is also a possible relationship between TPMT activity and the development of secondary malignancies. This article will review the effect of known SNPs on TPMT activity and consequences for thiopurine drug metabolism and cytotoxicity. The case for pre-treatment screening for TPMT status will also be addressed.