THE ABILITY to genetically engineer the mouse has allowed the development of an increasing number of murine models of carcinogenesis[l-4]. The power of these models lies in their consistency of tumorigenesis, wherein malignancy develops in a specific tissue (s), at a predictable age, and in some instances, from a particular type of premalignant lesion. Historically, two approaches have been used to generate families of cancer prone mice that heritably recapitulate oncogenes from normality to cancer: direct injection of pronuclei of one-cell embryos with DNA encoding dominant oncogenes (producing ‘transgenic mice’), or targeted disruption of tumour suppressor genes in embryonic stem cells which are subsequently injected into blastocysts (resulting in ‘gene knockout mice’). These technologies are being further refined, with the emergence of techniques for tissue specific gene knockouts and postnatal induction, or repression, of transgene expression. The reproducible induction of tumorigenesis in either transgenic or knockout mice has facilitated evaluation of the process of tumour development from normal cells in their natural tissue environment, revealing in many cases a multistep progression through discrete histological and temporal stages. Thus, in a number of cases, a series of premalignant stages has been identified, ranging from histological normality to hyperplasia, to varying degrees of dysplasia and carcinoma in S&L, which appear prior to the emergence of full blown cancers. These multistage models possess several features which have enhanced investigation of carcinogenesis, including:(i) the ability to biopsy premalignant lesions routinely, even very early ones, for biochemical, physiological and molecular genetic analyses, and for derivation of representative cultured cell lines;(ii) assessment of genetic complementation of carcinogenesis by generating double transgenic or composite transgenici knockout mice with altered expression of particular candidate genes;(iii) identification of genetic loci controlling stage-specific transitions by generating polymorphic genetic hybrids and constructing genetic and physical chromo-