G protein-coupled receptors (GPCRs) are membrane proteins and are an important drug target class responsible for over one-third of current therapeutics on the market. Adenosine receptors are broadly distributed in the human body and perform many vital functions. All four adenosine receptor subtypes (A1AR, A2aAR, A2BAR, and A3AR) are activated by endogenous small molecule adenosine. Therapeutically adenosine receptors have been pursued for the treatments of disorders associated with cardiovascular function, pain, inflammation and immunity, Parkinson’s disease, and many others. However, therapeutic targeting of adenosine receptors is challenging due to their broad distribution, high similarity between different adenosine receptor subtypes, and ability to simultaneously initiate multiple signaling cascades. Recently, x-ray crystallography and cryo-electron microscopy allowed us to gain insights into the molecular organization of multiple adenosine receptor subtypes bound to different small molecules. This structural information allowed us to understand the basis of selectivity between different receptor subtypes and mechanisms of action of their allosteric modulators and biased ligands.