Defects in mismatch repair contribute to development of approximately 15% of colon cancers and to origination of endometrial, gastric and other cancers. Tumors with defects in mismatch repair exhibit marked resistance to alkylators and a variety of anticancer agents that modify DNA to create substrates for the mismatch repair system. These altered drug responses appear to derive from requirements for mismatch repair proteins in signalling apoptosis, altered cell cycle checkpoint behaviour and/or loss of mismatch repair dependent toxicity arising from futile repair cycling. Altered repair mechanisms for mismatched substrates in mismatch repair defective tumors provide both challenges for development of tumor-phenotype-screening methodologies to assure appropriate therapy is administered for these cancers and foci for development of new therapy approaches that capitalize on modified drug responses in mismatch repair- defective cells. Copyright 1999 Harcourt Publishers Ltd.