Dengue fever is a mosquito-borne viral infection that affects over 300 million people each year. The dengue viral particle undergoes conformational changes during its maturation process, going from a 'spiky' immature form to a 'smooth' mature virion, whose cryo-EM structure is available; crystal structures of the envelope glycoprotein E have also been solved. One puzzling observation was that several epitopes recognized by neutralizing monoclonal antibodies are not exposed in the smooth, mature viral particle at room temperature (20 °C). Now work from Rossmann and colleagues may help solve this mystery. The authors incubated mature dengue virus particles at 37 °C, the temperature inside the human host, and then examined them by using cryo-EM. In contrast to the smooth particles seen at room temperature, the viral particles had a 'bumpy' appearance at 37 °C. These were different from the spiky immature form, which was the same at 20 or 37 °C. The transition from smooth to bumpy mature particles occurs between 31 and 35 °C, and this conformational change is irreversible. The authors determined the three-dimensional structure of the bumpy particle and fitted in the crystal structure of the glycoprotein-E dimer, which revealed a different arrangement of the dimers as compared to the smooth form. Notably, the bumpy structure is similar to a fusogenic intermediate form of dengue virus that was proposed over a decade ago. This indicates that the bumpy mature dengue virus is the predominant form in the human body and the one that actually infects human cells. Supporting this notion, the bumpy particles showed higher infectivity than did the smooth particles in a cell culture assay. This hypothesis needs to be further investigated, but a change to a 'ready-to-infect' form of dengue virus, triggered by the temperature shift upon entry into the human host, would constitute a remarkable example of host adaptation and have clear implications for vaccine development. (Proc.Natl.Acad.Sci.USAhttp://dx.doi.org/10.1073/pnas.1304300110,publishedonline8April2013)