The use of adrenaline in cardiac arrest resuscitation has been advocated since the 1960s. Laboratory studies and anecdotal experience showed improved rates of return of spontaneous circulation (ROSC) with the use of adrenaline at a dosage of approximately 0.01 mg/kg. This led to the widespread adoption of adrenaline administration during cardiac arrest into every resuscitation guideline for decades to come. Extensive laboratory studies characterized the beneficial physiological effects of adrenaline during cardiac arrest and closed-chest cardiopulmonary resuscitation (CC-CPR). Adrenaline administered during CC-CPR results in peripheral arterial vasoconstriction that raises the aortic pressure, particularly during the relaxation phase of CC-CPR. This increase in aortic pressure results in an increased aortic to right atrial pressure gradient that drives blood flow to the myocardium during CC-CPR. This pressure gradient is known as the coronary perfusion pressure (CPP) and has been shown to correlate with ROSC in both laboratory investigations and clinical studies. During the 1990s, the use of “high-dose” adrenaline showed increased rates of ROSC compared to “standard-dose” adrenaline. However, it was subsequently recognized that larger doses of adrenaline did not result in improved survival. Furthermore, questions have been raised as to whether or not “standard-dose” adrenaline improves survival from cardiac arrest. Recent meta-analyses have raised serious questions about the value of adrenaline, showing a benefit for achieving ROSC but no clear evidence of improved long-term survival. Controlled clinical trials to address this question are now underway. However, there is another important issue that needs to be addressed: the “route” of administration. With the growing interest in endovascular resuscitation, the use of intra-aortic adrenaline titration offers a means of rapidly and effectively delivering adrenaline to peripheral arterial effector sites while providing arterial pressure and CPP monitoring to guide titration of adrenaline doses to achieve an optimal hemodynamic effects while avoiding excessive adrenaline doses.