This paper examines the prospects for developing and implementing a binational water management agreement for the transboundary Santa Cruz River that crosses the US–Mexico boundary near the sister cities of Nogales, Sonora–Nogales, Arizona. After considering the geography, history, socio-economic context, and binational agreements affecting utilization of the Santa Cruz River, we review the conditions influencing recent binational progress on another transboundary river, the Tijuana River. Specifically, we ask what conditions created a favorable environment in which a binational agreement for management of the Tijuana River Watershed (TRW) was developed, what specific actions by relevant policy officials took place, and how the final agreement was reached. We then compare the dynamics that unfolded in the TRW with conditions in the Santa Cruz River to identify obstacles hindering progress towards achieving an International Boundary and Water Commission (IBWC) agreement (Minute) on shared management of the Santa Cruz River in its international reach. We find that the required political conditions that favored an agreement on the Tijuana River are not yet met on the Santa Cruz, although several favorable conditions do exist. We conclude with an assessment of current prospects for advancing binational cooperation that can inform discussion of how an IBWC Minute could be drafted to address water resource management issues in the Santa Cruz River Basin.