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Despite growth in faculty-led collaborations between the U.S. and Mexico, few empirical studies have comprehensively mapped the multiple factors that drive such academic collaborations. Through semi-structured interviews with 24 faculty from both countries, we explore these factors, while accounting for individuals’ experiences within professional, institutional, disciplinary, and regional contexts. We apply principles of network analysis to identify emergent relationships between these contexts and mechanisms by which collaborations are developed, sustained, or disenfranchised. We find institutional contexts, cross-cultural understanding, and personal relationships to be central drivers, while political and legal challenges, along with high teaching loads experienced by Mexican faculty present the greatest deterrents. We offer recommendations to policymakers and practitioners on how to strengthen the sustainability of these academic partnerships.