Pharmacologically induced ventilatory depression (PIVD) is a common postoperative complication with a spectrum of severity ranging from mild hypoventilation to severe ventilatory depression, potentially leading to anoxic brain injury and death. Recent studies, using continuous monitoring technologies, have revealed alarming rates of previously undetected severe episodes of postoperative ventilatory depression, rendering the recognition of such episodes by the standard intermittent assessment practice, quite problematic. This imprecise description of the epidemiologic landscape of PIVD has thus stymied efforts to understand better its pathophysiology and quantify relevant risk factors for this postoperative complication. The residual effects of various perianesthetic agents on ventilatory control, as well as the multiple interactions of these drugs with patient-related factors and phenotypes, make postoperative recovery of ventilation after surgery and anesthesia a highly complex physiological event. The sleep-wake, state-dependent variation in the control of ventilation seems to play a central role in the mechanisms potentially enhancing the risk for PIVD. Herein, we discuss emerging evidence regarding the epidemiology, risk factors, and potential mechanisms of PIVD.