Drugs are used during cardiopulmonary resuscitation (CPR) in association with chest compressions and ventilation. The main purpose of drugs during resuscitation is either to improve coronary perfusion pressure and myocardial perfusion in order to achieve return of spontaneous circulation (ROSC). The aim of this up-to-date review is to provide an overview of the main drugs used during cardiac arrest (CA), highlighting their historical context, pharmacology, and the data to support them. Epinephrine remains the only recommended vasopressor. Regardless of the controversy about optimal dosage and interval between doses in recent papers, epinephrine should be administered as early as possible to be the most effective in non-shockable rhythms. Despite inconsistent survival outcomes, amiodarone and lidocaine are the only two recommended antiarrhythmics to treat shockable rhythms after defibrillation. Beta-blockers have also been recently evaluated as antiarrhythmic drugs and show promising results but further evaluation is needed. Calcium, sodium bicarbonate, and magnesium are still widely used during resuscitation but have shown no benefit. Available data may even suggest a harmful effect and they are no longer recommended during routine CPR. In experimental studies, sodium nitroprusside showed an increase in survival and favorable neurological outcome when combined with enhanced CPR, but as of today, no clinical data is available. Finally, we review drug administration in pediatric CA. Epinephrine is recommended in pediatric CA and, although they have not shown any improvement in survival or neurological outcome, antiarrhythmic drugs have a 2b recommendation in the current guidelines for shockable rhythms.