Malaria is a devastating human disease, especially amongst the most vulnerable sub-populations of the world. It is important to understand how malaria parasites will respond to global elimination efforts. The emergence of drug resistance, dissemination of these traits to broader localities, and evolution of parasites into forms that may lead to greater pathology are of particular interest. The dominant human malaria parasite, P. falciparum, has been studied in Africa and SE Asia, but much remains to be learned about its patterns in South Asia. The other major human malaria parasite, P. vivax, continues to cause morbidity and mortality. However, phenotypic dissection of P. vivax traits and formal demonstration of variations between P. vivax isolates is restricted by our limited ability to culture them. In this renewal application, we will study: (1) the extent to which drug use and drug resistance shape the evolution of malaria parasites in India, (2) the extent to which vector distribution and characteristics effect transmission of drug resistance traits, and (3) how parasites’ response to immunity triggers novel interactions with host cells and leads to severe disease. India has both P. falciparum and P. vivax, has ecological conditions that are different and relevant, and may act as a bridge between SE Asia and eastern coast of E Africa. The MESA team partners will study malaria parasites in human hosts, mosquito vectors, and controlled laboratory studies after adaptation. Over the last five years, the team has successfully developed new clinical study sites in urban areas and community survey capabilities in remote, isolated parts of India. Our ability to work closely and collaboratively with government and non-governmental entities in India and provide professional opportunities for young, local scientists greatly facilitate our work. Key findings on evolution of drug resistance in malaria parasites, their interactions with mosquitoes, and ability to cause severe disease will be further pursed in this competitive renewal.