Every cell in the human brain possesses a unique genome that is the product of the accumulation of somatic mutations starting from the first postzygotic cell division and continuing throughout life. Somatic mosaicism in the human brain has been the focus of several recent efforts that took advantage of key technological innovations to start elucidating brain development, aging and disease directly in human tissue. On one side, somatic mutation occurring in progenitor cells has been used as a natural barcoding system to address cell phylogenies of clone formation and cell segregation in the brain lineage. On the other side, analyses of mutation rates and patterns in the genome of brain cells have revealed mechanisms of brain aging and disorder predisposition. In addition to the study of somatic mosaicism in the normal human brain, the contribution of somatic mutation has been investigated in both developmental neuropsychiatric and neurodegenerative disorders. This review starts with a methodological perspective on the study of somatic mosaicism to then cover the most recent findings in brain development and aging, and ends with the role of somatic mutations in brain disease. Thus, this review underlies what we have learned and what is still possible to discover by looking at somatic mosaicism in the brain genome.