Setting water policy depends fundamentally on the location of the supply and demand for water and the legal/institutional framework for water management. Within and across nations, laws and structures for water management decision making vary, often significantly. Recognizing these differences can aid in overcoming challenges inherent to the assessment and management of transboundary waters. This paper examines current binational efforts to develop the scientific information to support water management decision making along the United States-Mexico border. The particular focus is on transboundary aquifers along the border shared by the states of Arizona in the United States and Sonora in Mexico. Legislation enacted in the United States (Public Law 109–448) established a governmental-academic partnership to assess transboundary aquifers. The paper discusses the establishment of a working partnership between Mexico and the United States, which led to an official binational cooperative framework for transboundary assessment. It explains how the extensive effort to recognize and accommodate asymmetries in the underlying legal and regulatory frameworks for water management was essential to meeting the objectives of both countries. The focus of the binational investigations is briefly discussed. The paper concludes by noting the opportunities for additional cross-border scientific and water management collaboration should funding and institutional commitments continue.