The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full length (1-37) and truncated (7-37) forms of GLP-1 that can exist in an amidated form (GLP-1(1-36)NH(2) and GLP-1(7-36)NH(2)), and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms that are distributed across the receptor. We have investigated ten GLP-1R single nucleotide polymorphisms (SNPs), which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, ERK1/2 phosphorylation and intracellular Ca(2+ )mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligand- and pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the M(149) receptor variant. At the M(149) variant there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the C(333) variant peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the M(149) receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.