In healthy humans, seasonality has been documented in psychological variables, chronotype, sleep, feeding, metabolic and autonomic function, thermoregulation, neurotransmission, and hormonal response to stimulation, thus representing a relevant factor to account for, especially when considering the individual susceptibility to disease. Mood is largely recognized as one of the central aspects of human behavior influenced by seasonal variations. This historical notion, already mentioned in ancient medical reports, has been recently confirmed by fMRI findings, which showed that seasonality in human cognitive brain functions may influence affective control with annual variations. Thus, seasonality plays a major role in mood disorders, affecting psychopathology, and representing the behavioral correlate of a heightened sensitivity to factors influencing circannual rhythms in patients. Although the genetic basis of seasonality and seasonal affective disorder (SAD) has not been established so far, there is growing evidence that factors affecting the biological clock, such as gene polymorphisms of the core clock machinery and seasonal changes of the light-dark cycle, exert a marked influence on the behavior of patients affected by mood disorders. Here we review recent findings about the effects of individual gene variants on seasonality, mood, and psychopathological characteristics. © 2018 Garbazza and Benedetti.