The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain. Display omitted •3.2 Å resolution antagonist-bound structure of the adenosine A1 receptor solved•Major differences found in extracellular loop regions relative to the A2A structure•Drug selectivity is predominantly determined by binding site shape, not composition•Unexpectedly wide A1 receptor cavity reveals insights into allosteric drug actions The structure of the adenosine receptor A1 provides insights into the ways selectivity among adenosine receptor subtypes is achieved, opening avenues for design of subtype-specific drugs.