Most human malignancies are caused by somatic alterations within the cancer genome, leading to oncogene activation or tumor suppressor gene inactivation. The sequence of the human genome has enabled systematic approaches to identify cancer genome alterations, including point mutations, copy number increases and decreases, loss of allelic heterozygosity, and chromosome translocations. Systematic cancer genome analysis has recently led to the discovery of somatic mutations in the BRAF, PIK3CA, and EGFR genes, among others. With further development of targeted cancer therapies and improvement in genome analysis technology, genome-wide surveys of cancer will likely become tools for diagnosis as well as discovery.