Compounds that bind to allosteric sites offer many benefits over those which interact orthosterically. These include enhanced specificity, ability to operate only on receptor activation and reduced risk of overdose. A number of allosteric compounds have been identified in multiple disease areas including CNS (physiological and neuropathic disorders), metabolic disorder (diabetes and weight control), immunomodulation and cardiovascular indications. Allosteric approaches provide opportunities for new drug discovery by overcoming ligand incompatibility with certain drug scaffolds and improving the ability of small molecules drugs to modulate peptide ligand activity. In this study, we investigate the efficacy of a range of allosteric compounds using multiple GPCR readouts including arrestin recruitment, calcium mobilization, cAMP modulation and receptor internalization. Compounds were tested for ability to potentiate or down-regulate agonist responses using different approaches including EC50 shift analysis and residual agonist activity. Interactions were obtained in all three GPCR classes. Responses were obtained for multiple pathways demonstrating the utility for readouts involving either arrestin or second messenger signaling. Allosteric activity was also determined for receptor internalization and provides the means to examine the effect of allosterics to alter receptor cell surface population and activation kinetics.