A wide range of effective drugs is available for the treatment of major depression. The discovery of these agents has not always been the result of rational drug design. Tricyclic antidepressants formed the mainstay of treatment until the 1990s, and selective serotonin reuptake inhibitors (SSRIs) have dominated treatment over the last decade. However, the poor tolerability associated with tricyclic antidepressants and concerns about the efficacy of SSRIs has led to the search for alternative agents. Attention has focused on those drugs that affect norepinephrine and/or serotonin systems, with the recent introduction of a number of agents, including venlafaxine, milnacipran, nefazodone, mirtazapine, and reboxetine. Venlafaxine, which is the first in a new class of drugs known as serotonin and norepinephrine reuptake inhibitors, may be associated with an earlier onset of action and higher remission rates than SSRIs. It is hoped that the development of drugs with multiple sites of action will translate into improved clinical efficacy in the treatment of depression.