While there has been wide-ranging commitment to the One Health approach, its operationalisation has so far proven challenging. One Health calls upon the human, animal and environmental health sectors to cross professional, disciplinary and institutional boundaries, and to work in a more integrated fashion. At the global level, this paper argues that this vision is hindered by dysfunctions characterising current forms of global health governance (GHG), namely institutional proliferation, fragmentation, competition for scarce resources, lack of an overarching authority, and donor-driven vertical programmes. This has contributed, in part, to shortcomings in how One Health has been articulated to date. An agreed operational definition of One Health among key global institutions, efforts to build One Health institutions from the ground up, comparative case studies of what works or does not work institutionally, and high-level global support for research, training and career opportunities would all help to enable One Health to help remedy, and not be subsumed by, existing dysfunctions in GHG.