Alterations of the human MSH2 gene, a homologue of the bacterial MutS mismatch repair gene, co–segregate with the majority of hereditary non–polyposis colon cancer (HNPCC) cases. We have generated homozygous MSH2−/− mice. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio and bred through at least two generations. Starting at two months of age homozygous −/− mice began, with high frequency, to develop lymphoid tumours that contained microsatellite instabilities. These data establish a direct link between MSH2 deficiency and the pathogenesis of cancer. These mutant mice should be good models to study the progression of tumours and also to screen carcinogenic and anti–cancer agents.