Researchers have surveyed thousands of genomes of human tumors from smokers and nonsmokers and identified mutational signatures that are associated with tobacco smoke; for example, only cancer originating in tissues directly exposed to smoke showed a signature characteristic of a known tobacco carcinogen, report the researchers. Smoking is a risk factor for at least 17 types of cancer and claims the lives of more than six million people every year. Many of the carcinogens within cigarettes are thought to induce DNA damage. This increases the number of somatic mutations in healthy cells, which in turn increases a smoker's risk of acquiring cancer-causing mutations. However, the mechanisms by which tobacco smoke damages the genome and creates the mutations that may ultimately cause cancer are still not fully understood. Here, Ludmil B. Alexandrov et al. examined the genome sequences of 5,000 human tumors, representing 17 different types of cancer for which smoking is a risk factor. The researchers found that the mutations associated with tobacco smoke are more complex than previously thought. A subgroup of mutations relating to direct DNA damage by tobacco carcinogens, Signature 4, was particularly prominent in cancers derived from tissues directly exposed to smoke, such as the lungs and larynx, and occurred less often in cancers from indirectly exposed tissues, such as the bladder. Other signatures were attributed to the activity of a certain enzyme (a cytidine deaminase) that is known to be mutagenic. The most pervasively increased mutational signature, Signature 5, is of unknown origin; it was found in all cancer types and was "clocklike" in that the number of mutations attributable to this signature correlated with age at the time of diagnosis. Intriguingly, there were only small differences in DNA methylation in tumors of smokers versus nonsmokers, hinting that genetic mutations rather than epigenetic changes are the main mechanism by which smoking increases cancer risk. A Perspective by Gerd P. Pfeifer discusses these findings in greater detail.