At the age of 13, the 2:1 ratio becomes evident. It entails the fact that after puberty, twice as many females as compared to males suffer from depressive episodes. Much research has been conducted to highlight key contributing factors that aid in the onset and the timing of the 2:1 ratio. Many researchers emphasize hormonal influences and the onset of puberty as key contributors, with theories such as the gonadic theory andthe interactional hypothesis both highlighting the role of hormones in the existence and the emergence of the 2:1 ratio during adolescence. Furthermore, a large variety of researchers emphasize females increased stress sensitivity and stress reactivity as key contributors to the 2:1 ratio. Critically, research concerning hormonal- and stress-related factors will be included. However, an additional focus will be on neurodevelopmental sex differences. This, as brain-based sex differences have been paid too little attention in theories and models concerning the emergence of the 2:1 ratio during adolescence. Results from research conducted to unravel the mystery of sex differences within the adolescent brain emphasize the impact of sex hormones on the maturational sexual differentiation occurring within the adolescent brain. It has been hypothesized that increases in female adolescent depression might occur in accordance with upsurges in peripheral estrogen levels, during puberty. This seems to suggest that there is an interaction between the effects of circulating ovarian hormones in relation to both sexual differentiation in brain organization and depression susceptibility. Hence, the point of this essay is to delineate key contributing factors that potentially govern the existence and onset of the 2:1 ratio during adolescence by emphasizing the areas of (a) sex-based neurodevelopmental factors, (b) hormonal factors and (c) stress-related factors.