Half of women and 1/3 of men with angina and ischemia on stress testing have ischemia with no obstructive coronary artery disease (INOCA). These patients have quality of life (QoL) impairment comparable with patients with obstructive coronary artery disease. Clinicians generally treat INOCA with traditional antianginal agents despite previous studies demonstrating variable response to these medications. We performed a systematic review to evaluate the efficacy and safety of available pharmacologic therapies for INOCA. We systematically searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform in July 2017 for randomized controlled trials (RCTs) evaluating pharmacologic agents for INOCA. The primary outcome of interest was QoL. Secondary outcomes included subjective and objective efficacy measures and safety outcomes. We included 35 RCTs from 333 identified studies. Interventions that improved QoL with moderate-quality evidence included angiotensin-converting enzyme (ACE) inhibitor (±statin) and ranolazine. Low-to-very-low-quality evidence also suggests that ACE inhibitors, β blockers, calcium-channel blockers, nicorandil, ranolazine, and statins may decrease angina frequency and delay ischemia on stress testing. Other interventions, most notably nitrates, did not significantly improve any outcome. In conclusion, evidence for pharmacologic treatment of INOCA is generally poor, and higher-quality RCTs using a standardized definition of INOCA are needed. Moderate-quality evidence suggests that ACE inhibitors and ranolazine improve QoL. Other interventions had low-quality evidence or no evidence of efficacy.