Rescue Extracorporeal Life Support Programs based at non-cardiac surgery centers have unique needs to be able to ensure successful outcomes despite low patient volumes. In this paper we describe the important role simulation had in each stage of development, implementation, and maintenance of our pediatric Rescue ECLS Program. Systems-focused simulations were used to develop robust workflows, processes, and bundles. Simulation-based education targeted the acquisition and maintenance of clinical skills for individual team members, bringing together a multidisciplinary team of local clinicians who do not routinely perform pediatric cannulation related tasks. Translational simulation ensured continued improvement by addressing adverse events or latent safety threats observed during system-focused or educational simulations. Realism of all simulations was our priority, and was achieved through in situ simulations, participation of multidisciplinary teams, use of real equipment and medical supplies, and use of a high-fidelity cannulation manikin. This holistic simulation approach allowed us to overcome the barriers to high quality care, and maintain outcomes comparable to high volume centers. A similar approach can help other centers design simulation for their own Rescue ECLS Program, and can be translated to other high-risk and high-acuity critical care programs.