Cancer is a deadly disease, annually killing millions of people world-wide. Understanding the origin and progression of cancer are essential for designing efficacious treatments. While much is known about the shared factors of different types of cancer, it is becoming more evident that the cell-of-origin is the primary determinant of a tumor’s genetic and phenotypic characteristics. As such, many genes are frequently mutated in some cancer types, but not others, often with vast differences between anatomically related cancers. We hypothesize that most cancer-driving genes are tissue-specific because their effects are dependent upon the preexisting circuitry of the normal cell. The KRAS proto-oncogene is an exemplar of this behavior. KRAS is frequently mutated in several cancer types – namely colorectal, lung, and pancreatic adenocarcinomas and multiple myeloma – but rarely in most others. Further, the types of mutations acquired in the KRAS gene are tissue-specific, likely due to the differences in how their biochemical properties interact with the distinct cellular environments to drive cancer. In the first of three studies compiled here, a thorough characterization of the genetic contexts of the different KRAS mutations in these four cancer types was conducted using thousands of human tumor samples via an array of computational methods including predicting the most influential mutagenic forces and discovering mutation- and tissue-specific comutation networks. The following report statistically estimated the effects of mutant Kras (the homologous gene in the mouse, Mus musculus) on cell proliferation rates in ten tissues of genetically engineered mice to forward our understanding of the impact of oncogenic KRas signaling in different tissues. The final study explored the tissue-specificity of cancer genes by statistically modeling genome-wide CRISPR/Cas9 loss-of-function screens in a diverse array of cancer cell lines, identifying patterns of genetic dependency associated with cancer type. Each of these efforts leverages a distinct strategy for the investigation of tissue-specificity of cancer genes to reveal unique biological insights.