Background There is large and significant regional variation in out-of-hospital cardiac arrest (OHCA), and despite advances in treatment, survival remains low. The American Heart Association has called for the creation of integrated cardiac resuscitation systems of care capable of measuring and improving evidence-based care from bystanders through to hospital discharge. Methods The HeartRescue Project was initiated in 2010 by the Medtronic Foundation in collaboration with 5 academic medical centers and American Medical Response. The HeartRescue Project aims to develop regional cardiac resuscitation systems of care that will implement guideline-based best practice bystander, prehospital, and hospital care with standardized data reporting linked to outcomes. The primary goal is to improve collective OHCA survival by 50% over 5 years. Results The total population in the 5 participating states is 41.1 million. At baseline, the HeartRescue Project covers approximately 26.1 million people (63.6%) and has engaged 767 emergency medical services agencies and 269 hospitals. Data will be collected for quality improvement, to inform provider feedback, and serve to define effective strategies to improve cardiac arrest care. Conclusion The HeartRescue Project is the largest public health initiative of its kind focused entirely on cardiac arrest outcomes. The project is designed to significantly improve OHCA survival by implementing and measuring model systems of care for cardiac resuscitation.