AbstractCancer originates from a single ancestral cell that acquires a driver mutation, which confers a growth or survival advantage, followed by the acquisition of additional driver mutations by descendant cells. Recently, it has become evident that somatic cell mutations accumulate in normal tissues with aging and exposure to environmental factors, such as alcohol, smoking, and UV rays, increases the mutation rate. Clones harboring driver mutations expand with age, leading to tissue remodeling. Lineage analysis of myeloproliferative neoplasms and der(1;16)‐positive breast cancer revealed that driver mutations were acquired early in our lives and that the development of cancer takes decades, unveiling the previously unknown early process of cancer development. Evidence that clonal hematopoiesis affects various diseases, including nonneoplastic diseases, highlights the potential role of the identification and functional analysis of mutated clones in unraveling unknown pathologies. In this review, we summarize the recent updates on clonal expansion in normal tissues and the natural history of cancer revealed through lineage analysis of noncancerous and cancerous tissues.