Dengue virus transmission has increased dramatically in the past 2 decades, making this virus one of the most important mosquito-borne human pathogens. The emergence of dengue hemorrhagic fever in most tropical countries has made its control a public health priority, but no vaccines or treatments exist. Little is understood about dengue virus pathogenesis, because no other animals develop symptoms of disease, and research, therefore, has been limited to studies involving patients. Although epidemiologic and evolutionary studies have pointed to host and viral factors in determining disease outcome, only recently developed models could prove the importance of viral genotypes in causing severe epidemics. The influence of host immune status and mosquito vectorial capacity are also being tested in mathematical models to determine virus population dynamics. Therefore, new technologies are allowing us to better understand how specific virus variants cause more disease than others, and these virus variants should be targeted for detection, control, and treatment.