Approximately 13 million people reside in the 80 Mexican municipalities and 48 US counties located along the US-Mexico border; 86% of those people live in 14 pairs of sister cities – metropolitan areas divided by the frontier. Border residents share similar resources and environmental problems. Issues of great concern include air quality, the availability and quality of water, and animal control. The communities along the border are economically and socially interdependent, with more than a million legal north- and southbound crossings every day. The need to establish cooperation between Mexico and the USA to improve health and healthcare has led to many collaborative initiatives between public and private sectors. The authors describe the US-Mexico Border Health Strategic Initiative, a collaboration between 44 counties and municipalities along the border – the first time that the entire frontier region has been considered as a single epidemiological unit.