RAS genes are mutated in cancer more frequently than any other oncogene. Accordingly, RAS genes and the proteins they encode have been a major focus of cancer biologists for more than three decades. RAS genes encode small GTPases that regulate a variety of signaling pathways critical for cell growth. Whereas much has been learned about the biochemistry, cell biology and signaling of RAS proteins, they have denied attempts to develop drugs that directly target the GTPase. The genomic era has brought a huge new cache of data that relate to the biology of RAS and has led to a reinvigoration of efforts to develop inhibitors.