This review addresses the roles that both different gene polymorphisms involved in 5-HT signaling and the different 5-HT receptors (i.e. 5-HT1A, 5-HT1B, 5-HT4, and 5-HT7) may have in the pathophysiology of depression and the antidepressant response. This evidence concerns the gene HTR4 and major depressive disorder.