Cancer drug development is leading the way in exploiting molecular biological and genetic information to develop "personalized" medicine. The new paradigm is to develop agents that target the precise molecular pathology driving the progression of individual cancers. Drug developers have benefited from decades of academic cancer research and from investment in genomics, genetics and automation; their success is exemplified by high-profile drugs such as Herceptin (trastuzumab), Gleevec (imatinib), Tarceva (erlotinib) and Avastin (bevacizumab). However, only 5% of cancer drugs entering clinical trials reach marketing approval. Cancer remains a high unmet medical need, and many potential cancer targets remain undrugged. In this review we assess the status of the discovery and development of small-molecule cancer therapeutics. We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery.