In this study we provide the first characterization of a P. falciparum ligand essential for the invasion of the mosquito salivary glands. The critical ligand is MAEBL, which is a paralogue of EBA-175 and other erythrocyte binding proteins known to mediate an essential step for merozoite invasion of erythrocytes. Since alternative splicing of maebl is conserved among all Plasmodium species examined, it is not possible to know from previous studies what MAEBL isoform is essential for invasion. We find that only the transmembrane isoform of MAEBL is essential for the invasion of salivary glands, indicating an involvement of the cytoplasmic domain of MAEBL in the invasion process. No MAEBL knockout and ORF2 mutant sporozoites were present inside the salivary gland cells and sporozoites were not arrested in the invasion process on the surface of the glands. This observation that the MAEBL deficient mutants cannot attach to salivary Terbutaline Sulfate glands coincides with previous studies and Methoxamine hydrochloride contrasts with the data for TRAP in which TRAP deficient sporozoites were found on the surface of the salivary glands, but not inside the salivary cells. Importantly, sequence analysis shows that the MAEBL cytoplasmic domain lacks the penultimate tryptophan flanked by acidic residues at its C-terminus, which are known to be essential for TRAP binding to the parasite��s glideosome complex via aldolase. Although we found that there is an acidic motif near the C-terminus of P. falciparum MAEBL, these terminal residues are not fully conserved among MAEBL products of other Plasmodium species. The absence of these critical residues in the MAEBL cytoplasmic domain suggests that if this ligand interacts with aldolase or other components of the glideosome then this interaction has a molecular basis different from the TRAP-aldolase interaction. Based on its homology to the EBPs, which are critical for junction formation during merozoite invasion of erythrocytes, MAEBL may be important in a similar step for sporozoites invasion into the salivary gland cell. AMA1 has a major role in P. falciparum merozoite attachment and reorientation to erythrocytes and its high level of expression in sporozoites suggests that it may have a simi zlar role in the sporozoite invasion process.