Despite efforts to uncover genome variability confined to the human brain, genome composition of neurons remains a matter of conjecture in health and disease. Still, somatic neurogenomics continuously gives further insights into understanding of mechanisms for devastative psychiatric and neurological disorders. For instance, since somatic genetic mosaicism and genome instability affecting the brain dynamically change during the ontogeny, these phenomena are able to shape individual features of disease manifestation, course, and outcome. This review is dedicated to the involvement of genome instability in the pathogenesis of brain diseases. Genome/chromosome instability and somatic mosaicism mediating brain dysfunction may produce specific (personalized) manifestations and course of a brain disorder via genetic-environmental interactions. Consequently, genome instability in the brain has to be taken into account during the development of personalized therapeutic interventions in a wide spectrum of psychiatric and neurological disorders. Among the latters, the most striking are schizophrenia, Alzheimer’s diseases, and chromosome instability syndromes. Still, neurodevelopmental diseases (e.g., autism and intellectual disability) are to be investigated in the context of brain-specific genome instability.