The pathology of major depressive disorder (MDD) involves many physiological systems, including the estrogen system, the acetylcholine system and the hypothalamus-pituitary-adrenal axis (HPA-axis). This review explores the influence of these three systems on mood and memory with emphasis on involvement of the hippocampus. Behavioral and physiological symptoms of MDD, including cognitive and mood impairments, can be mitigated or exacerbated by estrogenic activity, as well as by modulations of the acetylcholine system. In addition, HPA-axis dysregulation is thought to contribute to the hippocampus-mediated cognitive impairments characteristic of MDD. Particularly, we focus on the role of selective estrogen receptors in HPA-axis function that affect hippocampal modulation of mood and memory. Increased estrogenic activity in the hippocampus is correlated with enhanced memory and mood, and increased estrogen receptor β activity has been shown to enhance mood and hippocampus-dependent memory independent of other estrogen receptors. Furthermore, we present evidence to support the utility of pharmacological agents that target estrogen receptor β for mood and memory enhancement for the treatment of MDD.