Cancer is a complex process in which the abnormalities of many genes appear to be involved. The combinatorial patterns of gene mutations may reveal the functional relations between genes and pathways in tumorigenesis as well as identify targets for treatment. We examined the patterns of somatic mutations of cancers from Catalog of Somatic Mutations in Cancer (COSMIC), a large‐scale database curated by the Wellcome Trust Sanger Institute. The frequently mutated genes are well‐known oncogenes and tumor suppressors that are involved in generic processes of cell‐cycle control, signal transduction, and stress responses. These “signatures” of gene mutations are heterogeneous when the cancers from different tissues are compared. Mutations in genes functioning in different pathways can occur in the same cancer (i.e., co‐occur), whereas those in genes functioning in the same pathway are rarely mutated in the same sample. This observation supports the view of tumorigenesis as derived from a process like Darwinian evolution. However, certain combinatorial mutational patterns violate these simple rules and demonstrate tissue‐specific variations. For instance, mutations of genes in the Ras and Wnt pathways tend to co‐occur in the large intestine but are mutually exclusive in cancers of the pancreas. The relationships between mutations in different samples of a cancer can also reveal the temporal orders of mutational events. In addition, the observed mutational patterns suggest candidates of new cosequencing targets that can either reveal novel patterns or validate the predictions deduced from existing patterns. These combinatorial mutational patterns provide guiding information for the ongoing cancer genome projects.—Yeang, C‐H., McCormick, F., Levine, A. Combinatorial patterns of somatic gene mutations in cancer. FASEB J. 22, 2605–2622 (2008)