Choice of an antidepressant medication is, in part, based on the side effects produced by a drug and the desire to avoid certain reactions in a particular patient. The clinician needs a reliable method of predicting which medications are most likely to produce specific untoward effects. Understanding the synaptic pharmacology of the most commonly used agents could serve as a tool for predicting possible side effects and drug-drug interactions. Antidepressant drugs alter neurotransmitter effects at nerve synapses, probably by blocking norepinephrine and serotonin reuptake, and blockade of neurotransmitter receptor sites – primarily the histamine H1 receptor, the muscarinic receptor, and the alpha-1-adrenoceptor. Possible clinical side effects related to some of these interactions include tachycardia, tremor, and (possibly) male sexual dysfunction (associated with norepinephrine reuptake blockade); sedation (associated with histamine H1 blockade); orthostatic hypotension, dizziness, and reflex tachycardia (associated with alpha-1-adrenoceptor blockade), and blurred vision, dry mouth, and memory dysfunction (associated with muscarinic receptor blockade). Pharmacologic data that demonstrate the potencies and selectivities of the antidepressant drugs for reuptake blockade and receptor site antagonism might allow the clinician to make an informed, rational choice of antidepressant therapy. This paper presents data on drug potencies and selectivities, and attempts to relate these data to anticipated side effects and drug-drug interactions.