Technical Abstract: Flowing from Mexico into the United States, the San Pedro Basin is the region’s only remaining perennial stream and one of the western hemisphere’s most ecologically diverse areas. Large mining, military, and municipal entities are major users of the same groundwater resources that maintain perennial flow in the San Pedro. This paper provides empirical evidence of the positive impacts on watershed management of scientists and policy researchers working closely with water managers and other stakeholders in a functioning HELP basin. We argue that transboundary cooperation in policymaking and water management is most effective when hydrologists help watershed groups understand the processes controlling water quality and quantity, and when managers and stakeholders connect these processes to social, economic and legal issues. We assess the distinctive nature of the Basin in terms of its physical and socioeconomic characteristics, as well as differences in institutional regulations, water law issues, and local implementation in Arizona and Sonora. We demonstrate how stakeholders and scientific researchers in both countries strive to balance ecosystem needs with human demands to create new, integrated basin management. Finally, we offer to the HELP agenda the accomplishments of this collaborative process—including the use of environmental-conflict-resolution tools—and the lessons learned from the San Pedro HELP Basin experience.