Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing characterized by intermittent partial or complete closure of the upper airway during sleep. If left untreated, OSA is associated with adverse cardiovascular outcomes such as hypertension, coronary heart disease, heart failure, cardiac arrhythmia, stroke, and death. Positive airway pressure (PAP) is often considered the first-line treatment for OSA. While PAP can be very effective in reducing the number of obstructive apneas and hypopneas, its impact on prevention of adverse cardiovascular consequences remains controversial, and treatment adherence is often poor. Hence, the necessity for novel treatment options to help those who cannot adhere to positive airway pressure treatment. Different classes of medications have been tested with regards to their effect on OSA severity. This review 1) provides an update on the epidemiology and pathophysiology of OSA, 2) outlines the mechanistic rationale for medication classes tested as OSA treatment and 3) discusses the effects of these medications on OSA. Several wake-promoting medications are approved for management of persistent sleepiness despite OSA treatment; discussion of these symptomatic treatments is outside the scope of this review. Herein, the authors review the current evidence for pharmacological management of OSA and provide future directions.