While most somatic mutations are functionally neutral, some can profoundly alter a cell’s phenotype and are associated with disease. Cancer is the best-known example, but other diseases including chronic liver disease, Huntington’s disease, and neurodevelopmental disorders are caused by somatic mutation or influence the selection of somatic clones. In this session, we will focus on how somatic mutations and evolution can lead to dysfunction, disease and treatment resistance, and why different populations are at different risk of somatic mutation-related diseases, and the challenges in diagnosing mosaic or tissue-specific disease.