Background: Regionalization is a system of organizing hospitals and providers to optimize care by matching patient needs with the appropriate healthcare resources. Regionalized care has been shown to improve outcomes in trauma, burn, stroke, STEMI, cardiac arrest, and NICU/OB care.Methods: This study was a comprehensive literature review to develop a classification- based, comparative review of existing regionalized systems of care by their components and characteristics. We performed a text-based analysis of the writing of the involved organizations (professional, regulatory, etc.) and interviews with the organizational leaders directly involved with regionalized systems of care. The scope of the review was three-fold: (1) to provide a summation of the available literature and established models of regionalized emergency care, (2) to identify the common core components of regionalized systems, and (3) to apply lessons about regional networks to sepsis care.Results: Regionalization in the US has followed a predictable pattern of development. Systems center on the delivery of time- or volume-sensitive care that is limited due to scarcity of resources, available facilities, or expertise. In response to perceived differential quality or inefficiency, professional organizations have published clinical guidelines and suggested regionalized tiered systems of facilities by resources and expectations of participation. These guidelines are used by government or third party certifying organizations to apply criteria to participating facilities. These efforts have been effective in establishing regionalized networks characterized by eight core components: triage/transfer protocols, resource-stratified networks, prevention/outreach/education, emergency preparedness, rehabilitation, internal/benchmarked data registries, performance improvement, and research.Conclusions: Several national models for regionalized systems of care are gaining traction and improving outcomes within the United States’ healthcare delivery system. Insights from this process hold promise to improve existing systems and establish new ones, notably in sepsis.