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Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax , the most geographically widespread yet neglected human malaria parasite. Endemic countries are expected to assess regularly the therapeutic efficacy of antimalarial drugs in use in order to adjust their malaria treatment policies, but proper funding and trained human resources are often lacking to execute relatively complex and expensive clinical studies, ideally complemented by ex vivo assays of drug resistance. Here we review the challenges for assessing in vivo P. vivax responses to commonly used antimalarials, especially chloroquine and primaquine, in the presence of confounding factors such as variable drug absorption, metabolism and interaction, and the risk of new infections following successful radical cure. We introduce a simple modeling approach to quantify the relative contribution of relapses and new infections to recurring parasitemias in clinical studies of hypnozoitocides. Finally, we examine recent methodological advances that may render ex vivo assays more practical and widely used to confirm P. vivax drug resistance phenotypes in endemic settings and review current approaches to the development of robust genetic markers for monitoring chloroquine resistance in P. vivax populations. [Display omitted] • Plasmodium vivax resistance to chloroquine may undermine malaria elimination efforts. • Plasmodium vivax resistance to schizontocides has been mostly monitored in therapeutic efficacy studies. • In vivo studies to determine the anti-relapse efficacy of primaquine are challenging to design and execute. • Ex vivo assays to determine Plasmodium vivax resistance to schizontocides remain limited to research settings. • Robust molecular markers to monitor Plasmodium vivax drug resistance are currently lacking. [ABSTRACT FROM AUTHOR]