In this chapter we will examine evidence concerning the emergence of an excess of unipolar depression in females during adolescence. We will also present new data from the Great Smoky Mountains Study (GSMS) in support of an approach that combines consideration of both the endocrinology of puberty and the effects of stress on depression. The phenomenon to be explained Numerous adult studies from around the world have documented that women have 1.5 to 3 times more current and lifetime unipolar depression than men (Bebbington, et al., 1981; Bland, Newman, and Orn, 1988a; Bland, Newman, and Orn, 1988b; Blazer, et al., 1994; Canino, et al., 1987; Cheng, 1989; Hwu, Yeh, and Chang, 1989; Kessler, et al., 1994; Kessler, et al., 1993; Lee, Han, and Choi, 1987; Weissman, et al., 1993; Weissman, et al., 1996; Weissman and Klerman, 1977; Wells, et al., 1989; Wittchen, et al., 1992). In later life (after age 55), the female excess of depressions probably diminishes; mostly on account of falling rates in women (Bebbington, 1996; Bebbington, et al., 1998; Jorm, 1987). Retrospective data from adults suggested that the female excess did not appear until adolescence (Burke, et al., 1990; Kessler, et al., 1993), and the child and adolescent epidemiological literature agrees that rates of unipolar depression in prepubertal girls are not higher than those in prepubertal boys (Anderson, et al., 1987; Angold, Costello, and Worthman, 1998; Angold, Costello, and Worthman, 1999; Angold and Rutter, 1992; Bird, et al.