ECMO is the implementation of the cardio-pulmonary bypass machine for prolonged periods of time to sustain systemic perfusion and gas exchange. This is an invaluable tool in the care of children with severe refractory cardio-circulatory and pulmonary failure, preferably in patients with potentially treatable and reversible cardiac disease. Development of the ECMO principles, although still not fully supported by evidence-based data, has allowed to progress from a salvage therapy to a more commonly used treatment to allow time for cardio-pulmonary recovery. Therefore, timely initiation of ECMO may impact prognosis. This has been the driving force followed by some centers that have continually available rapid sequence ECMO programs. Nevertheless, selection of the “appropriate” patients for ECMO remains a challenge, is continuously evolving and very institution-dependent. The principle of starting ECMO after failure of maximal medical therapy may be counterproductive. Decision to initiate ECMO in a cardiac patient, particularly after surgery often follows the instinctive judgment of the team. Literature suggests that early initiation of mechanical support in this patient population has been related to better outcomes and better hospital survival. Tendency to initiate ECMO in the early postoperative period or early throughout decompensation seeks to maintain adequate perfusion, to minimize ongoing myocardial insult and to enhance myocardial recovery. The latter may help create a favorable environment for myocardial recovery. Justification for ECMO initiation ought to be based on the patient’s lack of capacity to properly perfuse his tissues; hence the need to identify and use early markers of tissue perfusion anomalies.