Although cardiac arrest during airline flights is relatively uncommon, the unusual setting, limited resources, and the variability of the skills in medical volunteers present unique challenges. Survival in patients who suffer a witnessed arrest with a shockable rhythm who are treated promptly has improved since the advent of widely available automated external defibrillators (AEDs). In general, the chances of survival from an out-of-hospital cardiac arrest (OHCA) are greater when ventricular fibrillation (VF) is seen as the initial rhythm or if there is return of spontaneous circulation (ROSC). Not all in-flight cardiac arrests are witnessed because cabin crew or fellow passengers might simply assume that the victim is sleeping. Based upon a review of the literature on resuscitation after OHCA, we recommend that automatic external defibrillators be carried on all commercial airline flights, regardless of duration. Patients presenting with shockable rhythm (e.g., VF, unstable ventricular tachycardia) have the best prognosis for survival and usually require diversion of the aircraft for advanced cardiac life support (ACLS). Because diversion may require interruption of cardiopulmonary resuscitation (CPR) and may impact flight safety, the volunteer rescuer, cabin crew, flight crew, and medical consultation services should discuss the possible outcome and operational considerations before recommending a diversion for a patient with a nonshockable rhythm. The recommendations in this article were developed by members of the Air Transport Medicine and Aerospace Human Performance Committees and approved by the Council of the Aerospace Medical Association.Ruskin KJ, Ricaurte EM, Alves PM. Medical guidelines for airline travel: management of in-flight cardiac arrest. Aerosp Med Hum Perform. 2018; 89(8):754-759.