The invasion of host cells by malaria parasites represents an attractive target for therapeutic intervention. The role played by apical membrane antigen 1 (AMA1) in this process has been elucidated recently with the demonstration that AMA1 forms a complex with parasite rhoptry neck (RON) proteins as part of the moving junction that develops between the host cell and the invading parasite. Structural studies of AMA1 alone and in complexes with antibodies that inhibit host cell invasion have identified a conserved hydrophobic cleft that is essential to the assembly of the AMA1/RON complex. AMA1 is already established as an important candidate for inclusion in a malaria vaccine. Here we review both the structural details and functional significance of interactions at the hydrophobic cleft of AMA1, and argue that this feature of the protein represents an excellent target for the development of drugs that would block host cell invasion by malarial parasites.