Purpose of Review: Rabies is an ancient yet still neglected tropical disease (NTD). This review focuses upon highlights of recent research and peer-reviewed communications on the underestimated tropical burden of disease and its management due to the complicated dynamics of virulent viral species, diverse mammalian reservoirs, and tens of millions of exposed humans and animals – and how laboratory-based surveillance at each level informs upon pathogen spread and risks of transmission, for targeted prevention and control. Recent Findings: While both human and rabies animal cases in enzootic areas over the past 5 years were reported to PAHO/WHO and OIE by member countries, still there is a huge gap between these “official” data and the need for enhanced surveillance efforts to meet global program goals. Summary: A review of the complex aspects of rabies perpetuation in human, domestic animal, and wildlife communities, coupled with a high fatality rate despite the existence of efficacious biologics (but no therapeutics), warrants the need for a One Health approach toward detection via improved laboratory-based surveillance, with focal management at the viral source. More effective methods to prevent the spread of rabies from enzootic to free zones are needed.