This review presents the pharmacology of antidepressants as it relates to their effects on several neurotransmitters and their receptors. A theory about the mechanism of action of these drugs is presented, along with data for their affinities at human transporters for norepinephrine, serotonin, and dopamine, and at several different neurotransmitter receptors. This blockade by antidepressants of transporters and receptors is thought to relate to therapeutic and adverse effects of these compounds. Knowledge of this preclinical pharmacology of antidepressants will help the clinician understand the basis of certain adverse effects and drug interactions that can be avoided or minimized.