The etiology of most human cancers is unknown. Genetic inheritance and environmental factors are thought to have major roles, and for some types of cancer, exposure to carcinogens is a proven mechanism leading to tumorigenesis. Sequencing of entire cancer genomes has not only begun to provide clues regarding functionally relevant mutations, but has also paved the way towards understanding the initial exposures leading to DNA damage, repair and eventually to mutation of specific sequences within a cancer genome. Two recent studies of melanoma and small cell lung cancer exemplify what type of information can be gained from cancer genome sequencing.