Depressed patients consult with their primary care physician before engaging the services of a mental health care provider. Primary care physicians initiate more antidepressant pharmacotherapy than psychiatrists. Major depression has been estimated to have a 5% to 10% prevalence, with up to three times that percentage having significant subsyndromal depression symptoms. Patients frequently deny their depression, often neglecting to recognize their own somatic and cognitive/behavioral subjective symptoms, underestimating symptom severity, and possessing a reluctance to validate their existence because of social stigmata. There remains an underrecognition of the diagnosis of depression by primary care physicians. Often, depressed primary care patients present with somatic symptoms, which include gastrointestinal, skeletal muscle, and cardiovascular complaints, as opposed to describing nonsomatic criteria for depression. Elderly patients presenting with depression have an estimated prevalence of 5% to 50%, and the rate of suicide increases with age. In this patient group, depression may exist independently or secondary to insults or events. Major depressive disorders occur throughout the life cycle; however, the rate of major depression has increased, and the age of onset has become younger. Not uncommonly, complicating psychosocial factors coupled with multiple chronic disease states and physical pathology may mask the diagnosis of depression. Furthermore, up to 25% of extended care facility patients may satisfy the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for depression. Comorbid diseases and pharmacotherapy have been associated with secondary depression. Antidepressant pharmacotherapy combined with cognitive and behavioral therapy appears to offer the most benefit to the patient. Antidepressants independently act as catalysts to facilitate or correct the dysregulation of neurotransmission in depressed patients. The elderly present pharmacotherapeutic challenges based on a changing internal milieu in the absorption, distribution, metabolism, and elimination of most of the antidepressants. Polypharmacy may act to induce or inhibit the metabolism of substrate medication that the patient is currently using. A comprehensive list of cytochrome P450 interactions is provided. Generally the antidepressants display similarity in efficacy; however, effectiveness may be substantially different among and within antidepressant pharmacotherapeutic classes. The pharmacotherapeutic selection of antidepressants is a multifactorial cognitive process, including consideration of medication side effects and adverse effects and patient-specific factors. Other factors in this selection process include drug interaction potential, patient's prior drug response, and both the patient's concomitant pathology and pathophysiology and pharmacotherapy-mediated events. In conjunction with age-related, gender-related, and genetic factors, a full description of current serotonin pharmacotherapy-mediated events is provided. Included in this article are a review of traditional and newer antidepressants, their pharmacokinetics, their pharmacodynamics, and an elaborate interaction focus. Special emphasis is focused on individual antidepressants and class of antidepressants. This article provides comprehensive insights in perception, recognition, treatment, and the selection process involving antidepressants.