This chapter discusses models of unipolar mood disorder that incorporate both current neuroscience and clinical research. Severe major depressive disorder (MDD) is associated with higher basal cortisol secretion and higher peak levels, as well as dexamethasone resistance, indicating failure of feedback inhibition at both the higher stimulated cortisol levels and the lower resting cortisol levels. Post-traumatic stress disorder (PTSD) is associated with lower basal cortisol and increased glucocorticoid receptor (GCR) expression, indicating that the response to stress can be different in different disorders. The fundamental concept of the gene-environment interaction model is that whether a result of genes or early environmental trauma, or both, early life stress results in functional and structural changes in the brain that confer a life-long hyperactive stress response mediated by the hypothalamic pituitary adrenal (HPA) axis. Direct genetic effects or purely environmental effects may result in depressions.