Dengue is one of the most important emerging viruses, posing a threat to one-third of the global human population. Herein we show how the comparative analysis of gene sequence data has shed light on the origin and spread of dengue virus, as well as on the evolutionary processes that structure its genetic diversity. This reveals that dengue virus has a relatively recent evolutionary history, with the four serotypes originating approximately 1000 years ago and only establishing endemic transmission in humans in the last few hundred years. However, its place of origin remains uncertain as does the extent of genetic and phenotypic diversity present in the sylvatic (primate) transmission cycle. Although there is some evidence that viral strains differ in key phenotypic features such as virulence, and for positive selection at immunologically important sites, it seems likely that stochastic processes also play a major role in shaping viral genetic diversity, with lineage extinction a common occurrence. A more complete understanding of the evolution and epidemiology of dengue virus, particularly with respect to the aetiology of severe disease, will require large-scale prospective studies and the comparative analysis of complete genome sequences.