Virus transmission from wildlife to humans (“spillover”) causes a variety of emerging infections, from SARS-CoV-2 to Ebola. The notorious difficulty of anticipating spillover means that mitigation efforts predominately initiate only after viruses establish circulation in new host species. This reactive approach guarantees a sustained health burden from re-emerging viruses and preserves opportunities for novel viruses to establish in human populations. I will discuss multidisciplinary efforts to incorporate spillover prevention into the global health toolbox for zoonosis management. First, focusing on vampire bat-transmitted rabies, a zoonosis of economic and public health importance in Latin America, I will show how efforts to stop spillover by culling bats may backfire if deployed reactively and how virally-vectored, self-disseminating vaccines might reduce human and animal rabies risk by interrupting virus transmission within wild bat populations. Second, I will show how large scale, comparative studies of hundreds of viruses can challenge dogmas about viral origins and generate tools that enable evidence-based prioritization of viruses and hosts for laboratory experiments and surveillance. These studies illustrate how genomics, ecology and evolutionary biology can be integrated to reveal fundamental insights into natural host-virus interactions while forging the path from reactive to preventive management.