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Human cancer cell lines are widely used to model cancer but also have serious limitations. As an alternate approach, we have developed immortalized mouse epithelial cell model systems that are applicable to different tissue types and involve generation of immortalized cell lines that are genetically defined. By applying these model systems to mutant mice, we have extended the powerful approach of mouse genetics to in vitro analysis. By use of this model we have generated immortal epithelial cells that are either competent or deficient for apoptosis by different gain- and loss-of-function mutations that have revealed important mechanisms of tumor progression and treatment resistance. Furthermore, we have derived immortalized, isogenic mouse kidney, mammary, prostate, and ovarian epithelial cell lines to address the issues of tissue specificity. One of the major advantages of these immortalized mouse epithelial cell lines is the ability to perform biochemical analysis, screening, and further genetic manipulations. Moreover, the ability to generate tumor allografts in mice allows the integration of in vitro and in vivo approaches to delineate the mechanistic aspects of tumorigenesis. These model systems can be used effectively to determine the molecular requirements of epithelial tumorigenesis and tumor-promoting functions. This approach provides an efficient way to study the role of apoptosis in cancer and also enables the interrogation and identification of potential chemotherapeutic targets involving this pathway. Applying this technology to other mouse models can provide insight into additional aspects of oncogenesis.