Extracorporeal membrane oxygenation (ECMO) has been utilized in the care of critically ill patients for several decades now, saving thousands of lives in the process. As advances in ECMO technologies and management have evolved the utilization of ECMO in a larger variety of patients has been undertaken. However, a particularly difficult group of patients are those in which their underlying diagnosis is not known or fully understood. This group of patients poses particularly difficult decisions to be made, as ECMO is a particularly invasive and morbid therapy, which is not appropriate in all patients. These decisions are particularly difficult in neonatal and pediatric patients. Candidacy for ECMO therapy is continually evolving, and in pediatric patients underlying conditions are often not fully known prior to a child becoming critically ill. Discussed here are considerations for neonatal and pediatric patients with critical illness of uncertain etiology, and a framework for how to evaluate these patients with limited information.