With the human genome sequence at hand, it is now possible to sequence coding regions of cancer cell genomes to identify the mutated genes that drive tumor formation. The clinical importance of breast and colorectal cancer, together causing 14% of yearly cancer deaths, make these two tumor types suitable initial candidates for cancer genome sequencing. We recently surveyed more than half of the known human genes for somatic mutations in eleven breast and eleven colorectal cancers, and defined 122 and 69 genes, respectively, as candidate cancer genes in these two diseases. The study design provides a blueprint for future cancer genome sequencing efforts, validated by its ability to detect known and novel cancer genes. The findings shed light on heterogeneity between and within tumor types and provide novel research avenues for cancer biology.