Abstract Plasmodium vivax threatens half of the world’s population and is surprisingly resilient to on-going malaria elimination efforts, partially due to its unique characteristics and our poor understanding of its biology. Here, we propose to conduct state-of-the-art transcriptomic analyses using materials derived directly from Cambodian patients to rigorously assess the importance of red blood cell polymorphisms, host immunity and parasite factors in modulating the efficacy of red blood cell invasion and P. vivax intraerythrocytic development. Our studies will not only provide a better understanding of the fundamental molecular and cellular processes underlying blood stage P. vivax infections but will also provide a solid foundation to develop better malaria vaccines against this important but understudied human pathogen.