It is vitally important to identify the genetic determinants of complex brain-related disorders such as autism, dementia, mood disorders, and schizophrenia. However, the search for genes predisposing individuals to these illnesses has been hampered by their genetic and phenotypic complexity and by reliance upon phenomenologically based qualitative diagnostic systems. Neuroimaging endophenotypes are quantitative indicators of brain structure or function that index genetic liability for an illness. These indices will significantly improve gene discovery and help us to understand the functional consequences of specific genes at the level of systems neuroscience. Here, we review the feasibility of using neuroanatomic and neuropsychological measures as endophenotypes for brain-related disorders. Specifically, we examine specific indices of brain structure or function that are genetically influenced and associated with neurological and psychiatric illness. In addition, we review genetic approaches that capitalize on the use of quantitative traits, including those derived from brain images. Hum Brain Mapp, 2007. © 2007 Wiley-Liss, Inc.