Catecholamines, especially norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), have been implicated in the pathophysiology of depression. However, their exact roles and their interrelationship are not completely understood. Antidepressants have various effects on the body, including action at the neuronal synapses of the brain; the two most important of these effects are blockade of the reuptake of neurotransmitters, including NE, 5-HT, and dopamine, and blockade of certain neurotransmitter receptors. Currently available antidepressants may be classified as inhibitors of monoamine oxidase or as blockers of biogenic amine neurotransmitter reuptake, the latter best describing tricyclic antidepressants and selective 5-HT-reuptake inhibitors, because they block the reuptake of one or more neurotransmitters. However, recently introduced antidepressants, such as the 5-HT-NE-reuptake inhibitors, have synaptic effects that differ from those of older compounds. These synaptic effects are important in explaining certain side effects and drug-drug interactions associated with all classes of antidepresants. This article reviews the synaptic effects of marketed antidepressant agents to elucidate the anticipated side effects and drug-interaction potential of these agents.