Parathyroid Hormone (PTH) and PTH-related Protein (PTHrP) utilize the same G protein-coupled receptor – the PTH/PTHrP receptor or PTHR– to mediate their distinct biological actions. The extent to which the mechanisms by which the two ligands bind to the PTHR differ is unclear. We examined this question using several pharmacological and biophysical approaches. Kinetic dissociation and equilibrium binding assays revealed that the binding of ¹²⁵I-PTHrP(1–36) to the PTHR was more sensitive to GTPS (added to functionally uncouple PTHR|b7G protein complexes) than was the binding of ¹²⁵I-PTH(1–34) (75% maximum inhibition vs. 20%). Fluorescence resonance energy transfer-based kinetic analyses revealed that PTHrP(1–36) bound to the PTHR more slowly, and dissociated from it more rapidly than did PTH(1–34). The cAMP signaling response capacity of PTHrP(1–36) in cells decayed more rapidly than did that of PTH(1–34) (t_1/2 = 1h vs. 2h). Divergent residue five in the ligand: Ile in PTH and His in PTHrP, was identified as a key determinant of the altered receptor-interaction responses exhibited by the two peptides. We conclude that whereas PTH and PTHrP bind similarly to the G protein-coupled PTHR conformation (RG), PTH has a greater capacity to bind to the G protein-uncoupled conformation (R⁰), and hence, can produce cumulatively greater signaling responses (via R⁰RG isomerization), than can PTHrP. Such conformational selectivity may relate to the distinct modes by which PTH and PTHrP act biologically: endocrine vs. paracrine, and may help explain reported differences in the effects that the ligands have on calcium and bone metabolism when administered to humans.