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The contractile action of PZQ on the vasculature is mediated by the activation of host serotonergic 5-HT<jats:sub>2B<\/jats:sub> receptors (5-HT<jats:sub>2B<\/jats:sub>Rs). However, the molecular basis for PZQ interaction with these targets and the location of these 5-HT<jats:sub>2B<\/jats:sub> receptors in the vessel wall have not been experimentally defined. Evaluation of a PZQ docking pose within the 5-HT<jats:sub>2B<\/jats:sub>R orthosteric site, using both Ca<jats:sup>2+<\/jats:sup> reporter and bioluminescence resonance energy transfer (BRET) assays, identified residues F340<jats:sup>6.51<\/jats:sup> and F341<jats:sup>6.52<\/jats:sup> (transmembrane helix 6, TM6) as well as L209<jats:sup>EL2<\/jats:sup> (extracellular loop 2) as critical for PZQ-mediated agonist activity. A key determinant of PZQ selectivity for the 5-HT<jats:sub>2B<\/jats:sub> receptor over the 5-HT<jats:sub>2A<\/jats:sub>\/<jats:sub>2C<\/jats:sub> receptors was determined by M218<jats:sup>5.39<\/jats:sup> in transmembrane helix 5 (TM5) of the orthosteric site. Mutation of this residue to valine (M218V), as found in 5-HT<jats:sub>2A<\/jats:sub> and 5-HT<jats:sub>2C<\/jats:sub>, decreased PZQ agonist activity, whereas the reciprocal mutation (V215M) in 5-HT<jats:sub>2C<\/jats:sub> increased PZQ activity. Two-photon imaging in intact mesenteric arterial strips visualized PZQ-evoked Ca<jats:sup>2+<\/jats:sup> transients within the smooth muscle cells of the vessel wall. PZQ also triggered cytoplasmic Ca<jats:sup>2+<\/jats:sup> signals in arterial smooth muscle cells in primary culture that were isolated from mesenteric blood vessels. 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