This article offers a multilevel perspective on resilience to depression, with a focus on interactions among social and neurobehavioral systems involved in emotional reactivity and regulation. We discuss models of cross-contextual mediation and moderation by which the social context influences or modifies the effects of resilience processes at the biological level, or the biological context influences or modifies the effects of resilience processes at the social level. We highlight the socialization of emotion regulation as a candidate process contributing to resilience against depression at the social context level. We discuss several factors and their interactions across levels—including genetic factors, stress reactivity, positive affect, neural systems of reward, and sleep—as candidate processes contributing to resilience against depression at the neurobehavioral level. We then present some preliminary supportive findings from two studies of children and adolescents at high risk for depression. Study 1 shows that elevated neighborhood level adversity has the potential to constrain or limit the benefits of protective factors at other levels. Study 2 indicates that ease and quickness in falling asleep and a greater amount of time in deep Stage 4 sleep may be protective against the development of depressive disorders for children. The paper concludes with a discussion of clinical implications of this approach.