Although epinephrine has been a cornerstone in resuscitation medicine for over 60 years, its use had never been thoroughly studied until recently, probably because the benefits of epinephrine seemed so obvious. The vasoconstriction of arterioles mediated by α-adrenergic receptors, leading to a higher coronary blood flow during chest compression, which in turn leads to a recovery of the spontaneous circulation, was reason enough for epinephrine to have been given its prominent role. A number of studies in the past 10 years, both randomized trials and large observational studies, have failed to show improved outcomes in patients with out-of-hospital cardiac arrest who had received epinephrine. The PARAMEDIC2 trial was published recently, with 4,015 patients receiving parenteral epinephrine and 3,999 receiving placebo. This study showed a survival benefit for epinephrine; however, there was no significant survival with good neurological outcome. The reasons for this may be related to a disturbed cerebral microcirculation and decreased blood flow in the carotid artery, and to epinephrine-mediated platelet activation, with an increased risk of thrombosis.