In our knowledge-driven era, multiple and mutual benefits accrue from transnational research linkages. The article identifies important directions in transnational research collaborations involving U.S. universities revealed by key dimensions of 369 projects profiled on a U.S. higher-education association's database. Project initiators, principal research fields, regional and country distributions, and the sources and amounts of funding for different types of transnational research activity are selected for analysis. The balanced total portfolio of reported current research projects by region suggests that U.S. university principal investigators increasingly recognize the value of collaborative knowledge generation in the Global South as well as in other OECD countries. The data also show concentrations in the distribution of transnational research projects by principal field of activity that could exacerbate intra-regional asymmetries. The multi-institutional data draw attention to the often unnoticed, but vital, role that higher-education institutions play in supporting transnational research endeavors that address issues of current and future global concern. The conclusion considers wider implications for higher-education involvement in transnational knowledge generation and calls for increased symmetry in collaborative research ventures.