The paper discusses the challenges in identifying genetic factors for major depression (MDD) and proposes endophenotypes as a way to improve phenotypic definitions. Endophenotypes are internal traits that bridge the gap between genes and disease, offering more specific and measurable characteristics than traditional clinical phenotypes. The authors propose two levels of endophenotypes: psychopathological and biological. Psychopathological endophenotypes include mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. Biological endophenotypes include REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical (HPA) axis, and CRH systems, and intracellular signal transduction endophenotypes. The authors argue that these endophenotypes are more specific, stable, heritable, and biologically plausible than traditional phenotypes. They also emphasize the need for a new classification system to reduce the heterogeneity of depression, which has hindered genetic and neurobiological research. The paper reviews the literature on the biological and genetic basis of MDD, highlighting the associations between endophenotypes and genes. It concludes that endophenotypes may help elucidate the genetic and neurobiological basis of MDD by providing more accurate and measurable traits.The paper discusses the challenges in identifying genetic factors for major depression (MDD) and proposes endophenotypes as a way to improve phenotypic definitions. Endophenotypes are internal traits that bridge the gap between genes and disease, offering more specific and measurable characteristics than traditional clinical phenotypes. The authors propose two levels of endophenotypes: psychopathological and biological. Psychopathological endophenotypes include mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. Biological endophenotypes include REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical (HPA) axis, and CRH systems, and intracellular signal transduction endophenotypes. The authors argue that these endophenotypes are more specific, stable, heritable, and biologically plausible than traditional phenotypes. They also emphasize the need for a new classification system to reduce the heterogeneity of depression, which has hindered genetic and neurobiological research. The paper reviews the literature on the biological and genetic basis of MDD, highlighting the associations between endophenotypes and genes. It concludes that endophenotypes may help elucidate the genetic and neurobiological basis of MDD by providing more accurate and measurable traits.