This chapter highlights studies on excessive daytime sleepiness (EDS) and depression within the framework of human sleep and chronobiology. It provides an outlook of chronobiological underpinnings of this relationship in order to provide insights and candidates for chronobiological management. Sleepiness may reflect the waning of processes maintaining wakefulness and/or may result from distinct neural systems acting to promote sleep. Recent imaging studies have shed new light on the neurobiological basis of depression. Clinical rating scales measuring depression often inquire about fatigue and tiredness. On a pharmacological domain, there is emerging evidence that the circadian system is implicated in some of the treatment mechanisms, such as lithium therapy for bipolar depression. Insights on the link among EDS, depression and chronobiology can provide a better comprehension of this sleep-wake disturbance, together with promising therapeutic managements.