Abstract Plasmodium vivax parasites threaten half of the world’s population and are surprisingly resilient to on-going malaria elimination efforts, partially due to their ability to remain dormant in the liver as hypnozoites for weeks or months. Here, we propose to conduct state-of-the-art transcriptomic, epigenomic and lipidomic analyses using materials collected from non-human primates infected with P. vivax, and in vitro infections of human hepatocytes with patient-derived P. vivax sporozoites. Our analyses will provide a comprehensive perspective on the molecular and cellular mechanisms underlying the onset, maintenance and exit of P. vivax dormancy, and well as on the response of the host, from the infected hepatocytes to the organ- and organism-wide responses. Our findings will not only provide a better understanding of the fundamental processes underlying the fate and development of liver-stage P. vivax parasites but will also provide a solid foundation to develop better malaria vaccines and therapies against this important but understudied human pathogen.