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Numerous positive and negative allosteric modulators (PAMs and NAMs) of Class C G protein-coupled receptors (GPCRs) have been developed as valuable preclinical pharmacological tools and therapeutic agents. While many Class C GPCR allosteric modulators have undergone subtype selectivity screening, most assay paradigms have failed to perform rigorous pharmacological assessment. Utilizing mGlu5 as a representative Class C GPCR, we tested the hypothesis that allosteric modulator selectivity was based on cooperativity rather than affinity. Specifically, we aimed to identify ligands that bound to mGlu5 but exhibited neutral cooperativity with mGlu5 agonists. We additionally evaluated the potential for these ligands to exhibit biased pharmacology. Radioligand binding, intracellular calcium (iCa2+) mobilization and inositol monophosphate (IP1) accumulation assays were undertaken in HEK293A cells expressing low levels of rat mGlu5 (HEK293A-mGlu5-low) for diverse allosteric chemotypes. Numerous "non-mGlu5" Class C GPCR allosteric modulators incompletely displaced allosteric mGlu5 radioligand [3H]methoxy-PEPy binding, consistent with a negative allosteric interaction. Affinity estimates for CPCCOEt (mGlu1 ligand), PHCCC (mGlu4 ligand), GS39783 (GABAB ligand), AZ012216052 (mGlu8 ligand), and CGP7930 (GABAB ligand) at mGlu5 were within 10-fold of their target receptor. The majority of Class C GPCR allosteric modulators had neutral cooperativity with both orthosteric and allosteric mGlu5 agonists in functional assays. However, NPS2143 (CaSR NAM), cinacalcet (CaSR PAM), CGP7930 and AZ012216052 were partial mGlu5 agonists for IP1 accumulation, but not iCa2+ mobilization. By employing mGlu5 as a model Class C GPCR, we find that for many Class C GPCR allosteric modulators, subtype selectivity is driven by cooperativity, and misinterpreted due to unappreciated bias.