Most antidepressant drugs prescribed today have been available for decades. Nonetheless, their mechanism of action in treating depression has remained elusive. On the basis of neurochemical studies in laboratory animals, hypotheses explaining their therapeutic effects have been formulated. The most attractive of these theories involves antidepressant-induced changes in the sensitivity of certain catecholamine and serotonergic receptors in the brain. Support for this hypothesis from clinical studies has been difficult to obtain. Pharmacologic studies of antidepressant drugs, however, indicate the involvement of blockade of neuronal uptake systems for norepinephrine and serotonin and blockade of many receptors for neurotransmitters. These properties of antidepressants can explain some of their adverse effects and certain interactions with other drugs.