Managing out-of-hospital cardiac arrest involves unique challenges, including delays in the initiation of advanced interventions and a limited number of trained personnel on scene. Recent out-of-hospital randomized controlled trials, systematic reviews, and metaanalyses provide key insights into what interventions are best proven to positively impact patient outcomes from out-of-hospital cardiac arrest. We review the literature on medications used in out-of-hospital cardiac arrest and summarize evidence-based guidelines from the American Heart Association that form the basis for most emergency medical services cardiac arrest protocols across the United States.