Despite clear evidence of an intimate connection between sleep, major depressive disorders (MDD) and gender, few studies have explored gender differences in either sleep or in wakefulness in patients as a means of better understanding the psychogenic components of MDD. Indeed, few sleep studies focus on characterising gender differences in any population. This paper will present a review of the literature on gender differences in sleep and depression. The theoretical and clinical implications of the findings will also be discussed. The premise of the present review is that there is an inherent increased vulnerability to depression in women that arises out of basic gender differences in brain organisation and state regulation, particularly in response to a “biological challenge” during sleep. It is argued that the inherent properties of organisation and regulation of sleep EEG in healthy men and women, elicited under challenge conditions, show gender-specific vulnerability to organisational abnormalities that model homeostatic abnormalities in depressed men and women and contribute to the genesis of depression. 2001 Harcourt Publishers Ltd