Rabies, caused by a single-stranded RNA virus, is arguably the most important viral zoonotic disease worldwide. Although endemic throughout many regions for millennia, rabies is also undergoing epidemic expansion, often quite rapid, among wildlife populations across regions of Europe and North America. A current rabies epizootic in North America is largely attributable to the accidental introduction of a particularly well-adapted virus variant into a naive raccoon population along the Virginia/West Virginia border in the mid-1970s. We have used the extant database on the spatial and temporal occurrence of rabid raccoons across the eastern United States to construct predictive models of disease spread and have tied patterns of emergence to local environmental variables, genetic heterogeneity, and host specificity. Rabies will continue to be a remarkable model system for exploring basic issues in the temporal and spatial dynamics of expanding infectious diseases and examining ties between disease population ecology and evolutionary genetics at both micro- and macro-evolutionary time scales.