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Tumor suppressor genes are a class of genes found mutated on both alleles in tumor cells. They are usually implicated in DNA repair, cell-cycle progression, differentiation, and apoptosis. Their loss of function is involved in the development of malignancies. Many of these tumor suppressor genes are also found mutated in familial cancers. To better understand the development of tumors that have lost the functions of these tumor suppressor genes, we have generated animal models by targeting these genes in the germline of mice. Many of these mutations, when bred to homozygosity, however, are embryonic lethals in the mice. Consequently, conditional knockouts of these genes are used to study their functions. They include tissue-specific deletions and inducible knockouts. Progress in these genetic manipulations to study tumor development in animals with mutations of BRCA1, DPC4, and PTEN will be described.