Most cases of complex human diseases arise sporadically. However, usually there is a significant level of familial aggregation of risk and genetic mapping has identified the responsible gene in a few mendelian cases. Although a disease can be causally genetic, intensified mapping efforts have so far been unable to identify genes that account for more than a small fraction of the familial risk, perhaps because the responsible variation arises by somatic mutation (SM). SM explains the kind of epidemiological pattern seen in cancer, and might have a comparable role in many other diseases. For example, in epilepsy, which has largely defied mapping analysis, the underlying disease pathology, undamped neuronal signaling, is closely connected to gene function. Better technologies to detect and characterize SM are becoming available. However, until it is studied directly, SM will remain a cryptic etiological force, even for diseases that are essentially ‘genetic'.