The incidence of vector-borne diseases is rising as deforestation, climate change, and globalization bring humans in contact with arthropods that can transmit pathogens. In particular, incidence of American Cutaneous Leishmaniasis (ACL), a parasitic disease transmitted by sandflies, is increasing as previously intact habitats are cleared for agriculture and urban areas, potentially bringing people into contact with vectors and reservoir hosts. Previous evidence has identified dozens of sandfly species that have been infected with and/or transmit Leishmania parasites. However, there is an incomplete understanding of which sandfly species transmit the parasite, complicating efforts to limit disease spread. Here, we apply machine learning models (boosted regression trees) to leverage biological and geographical traits of known sandfly vectors to predict potential vectors. Additionally, we generate trait profiles of confirmed vectors and identify important factors in transmission. Our model performed well with an average out of sample accuracy of 86%. The models predict that synanthropic sandflies living in areas with greater canopy height, less human modification, and within an optimal range of rainfall are more likely to be Leishmania vectors. We also observed that generalist sandflies that are able to inhabit many different ecoregions are more likely to transmit the parasite. Our results suggest that Psychodopygus amazonensis and Nyssomia antunesi are unidentified potential vectors, and should be the focus of sampling and research efforts. Overall, we found that our machine learning approach provides valuable information for Leishmania surveillance and management in an otherwise complex and data sparse system.Author SummaryAmerican Cutaneous Leishmaniasis (ACL) is a neglected parasitic disease transmitted by sandflies in Latin America. There is an incomplete understanding of which sandfly species transmit the parasite, complicating efforts to limit disease spread. In this study, the authors created a database of sandfly traits, then used predictive models to determine important factors in disease transmission and how different climate and environmental variables affect ACL transmission. The models suggest that transmission occurs at the interface between domestic habitats and well-preserved forests. The authors also generate predictions of which sandflies might be transmitting the parasite that are not known vectors at the time, specifically Psychodopygus amazonensis and Nyssomia antunesi. This new knowledge can lead to a better understanding of the system of transmission, and can point to possible hotspots of the disease. The analysis can also help direct researchers to areas of interest for sampling studies, as well as specific sandflies to focus their effort on.