Summary While a few cancer genes are mutated in a high proportion of tumors of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalog of cancer genes, we analyzed somatic point mutations in exome sequence from 4,742 tumor-normal pairs across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumor types. Our analysis also identified 33 genes not previously known to be significantly mutated, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes, mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5000 samples per tumor type, depending on background mutation rate. The results help guide the next stage of cancer genomics.