Many drug discovery efforts focus on G protein-coupled receptors (GPCRs), a class of receptors that regulate many physiological processes and account for over one-third of current prescription medicines approved by the FDA. The adenosine A1 receptor (A1R) is a class A GPCR that mediates the action of the cytoprotective purine nucleoside adenosine and preferentially couples to the inhibitory Gi/o family of heterotrimeric G-proteins. The A1R is a particularly promising GPCR target for drug discovery, with activation of this receptor therapeutically desirable for both cardiovascular disease and neuropathic pain. However, the progression of subtype selective A1R agonists in the clinic has been hindered primarily by on-target side effects. New promising avenues for pharmacological targeting of this receptor include the development of allosteric modulators and/or signal pathway ‘biased’ agonists. We have previously solved a 3.6 Å structure of the human A1R in complex with adenosine and heterotrimeric Gi2-protein determined by cryo-electron microscopy. Recently, we have solved two new structures of the same A1R-Gi2 complex to reveal the first allosteric binding site for a synthetic small molecule (MIPS521) at the A1R and identify an atypical binding pose for a ‘biased’ A1R agonist (VCP746). Insights from these structures provide the first insights into the mechanisms underlying allosterism and biased agonism at this important therapeutic target.