The available hypotheses or explanations for the urbanization of American visceral leishmaniasis are insufficient. An alternative hypothesis is that changes in the ecology and biology of the vector, Lutzomyia longipalpis, might explain all the new urban epidemiological features of the disease. To tackle the knowledge gaps in this process, certain key research areas need to be prioritized: the role of dogs in expanding transmission in cities, community trials to evaluate new insecticides, and research on the ecological and molecular determinants of Leishmania chagasi transmission. Investment of public funds should focus on the development of a human vaccine, since such a vaccine now appears to be within reach. Even small effects from a vaccine could substantially reduce the impact of the disease, which in the last quarter century has challenged and defeated both the scientific community and the public health field around the world.