Sexual dysfunction related to antidepressants, particularly serotonin reuptake inhibitors is a major cause of premature treatment discontinuation. This places patients at increased risk for recurrence, relapse, chronicity, and mortality (eg, suicide). The clinical assessment requires a comprehensive evaluation of sexual function, including libido, arousal, orgasm, and resolution prior to affective disorder, disturbances associated with the emergence of depression, and changes or dysfunctions associated with antidepressant treatment. Other factors to be included for evaluating sexual dysfunction include inquiry for concurrent medical conditions, somatic treatments, lifestyle risk factors, and response to antidepressants. Current treatment approaches to antidepressant-associated sexual dysfunction have relied on open-label reports, literature reviews, and clinical wisdom. Without double-blind, placebo-controlled studies to support them, too much non-evidence-based treatment may be offered to patients. Advances into nonadrenergic-noncholinergic novel signal transduction, specifically phosphodiesterase type-5 inhibitors, offer new opportunities for developing evidence-based treatments for this side effect and improving depression disease management outcomes.