Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes (IEs) accumulating in the placenta and has dire consequences for both mother and child. The multi-domain antigen VAR2CSA confers specific adhesion of IEs to chondroitin sulphate A (CSA) in the placenta, and is the leading PAM vaccine candidate. Recent data from different laboratories show that the binding properties of individual VAR2CSA domains do not reflect the native CSA-specific adhesion of IEs, which questions the relevance of the information obtained from single domain binding assays and co-crystallization experiments. Here, we discuss the implications of these findings for VAR2CSA vaccine development and highlight the need for studying the native structure of this protein.