The development of resistance of animal tumour tissue in vivo toward pyrimidine and purine analogues is generally accounted for by a process of mutation and selection, although in some cases metabolic alterations leading to the emergence of resistant cells are epigenetic. Neoplastic cells may develop resistance in vitro toward a pyrimidine analogue while they carry a repressed oncogenic virus genome; upon withdrawal of the drug, the synthesis of virus particles appears. Following the administration of one analogue, resistance in various tumours develops in different patterns. The underlying biochemical lesions resulting in the emergence of resistance following 6-azauridine, 5-fluorouracil and 5-azacytidine is the deletion of uridine kinase which is the rate-limiting enzyme along the salvage pathway. There is an indication that at least in some cases the decreased activity of this enzyme is due to its structural and/or conformational changes. The development of resistance toward 5-iodo- and 5-bromo-2′-deoxyuridine is accompanied by the deletion of thymidine kinase activity; resistance towards cytosine arabinoside is associated with the deletion of deoxycytidine kinase. Different means of circumventing the emergence of resistance are surveyed.