Introduction: Numerous challenges have hampered developing an anti-malarial vaccine against the most widespread malarial parasite worldwide: Plasmodium vivax. Despite the progress achieved in studying proteins in short-term in vitro culture or in experimental models, there is still no clear method for defining which antigens or their regions should be prioritized for including them in a vaccine. Areas covered: The methods used by research groups so far which have focused on the functional analysis of P. vivax blood stage antigens have been reviewed here. A logical strategy orientated toward resolving two of the most commonly occurring problems in designing vaccines against this species has thus been proposed (i.e. the search for candidates and evaluating/ascertaining their functional role in the invasion of such molecules). Expert commentary: Advances in knowledge regarding P. vivax biology have been extremely slow. Only two key receptor–ligand interactions concerning merozoite entry to reticulocytes have been reported during the last 20 years: PvDBP1-DARC and PvRBP2b-CD71. Despite increasing knowledge about the parasite’s intimate preference for its host cells, it has yet to be determined which regions of the merozoite molecules characterized to date meet the requirement of inducing protective immune responses effectively blocking heterologous parasite entry to human cells.