The invasion of Plasmodium falciparum merozoites into the erythrocytes of its human host involves a myriad of well-characterised receptor-ligand interactions yet little is known of their hierarchy or their relationship to the distinct morphological and physiological events that characterise this process. Here, we examine this using real-time imaging in combination with different methods of effectively ablating 3 distinct receptor-ligand interactions; the EBA/Rh alternate pathways, the Rh5-Basigin (BSG) interaction and the AMA1-RON2 interaction. We show that these 3 events are distinct and occur in the aforementioned order, beginning with the EBA/Rh alternate pathways involved in little early contact, erythrocyte deformation and motor dependent re-orientation. Next, the Rh5- BSG interaction is required to anchor the merozoite apical end and to trigger dehydration of the target erythrocyte. This in turn leads to an irreversible tight-junction involving AMA1-RON2 and is required for erythrocyte penetration to commence. Following blockage of the Rh5-BSG interaction, merozoites can still deform their target erythrocytes but cannot trigger dehydration whereas when downstream AMA1-RON2 interactions are blocked, deformation and dehydration occur. This leads us to speculate that Rh5-BSG is required to stimulate rhoptry release which permeabilises the erythrocyte surface allowing calcium entry which leads to erythrocyte dehydration. Unexpectedly, the source of this calcium appears to be from secretory organelles of the invading merozoite, possibly rhoptries. This study provides a rational basis to combine key vaccine candidates for the control of P. falciparum malaria blood-stages.