The development of ligands for the A3 adenosine receptor (AR) has been directed mainly by traditional medicinal chemistry, but the influence of structure-based approaches is increasing. Rhodopsin-based homology modeling had been used for many years to obtain three-dimensional models of the A3AR, and different A3AR models have been published describing the hypothetical interactions with known A3AR ligands having different chemical scaffolds. The recently published structure of the human A2AAR provides a new template for GPCR modeling, however even use of the A2AAR as a template for modeling other AR subtypes is still imprecise. The models compared here are based on bovine rhodopsin, the human β2-adrenergic receptor, and the A2AAR as templates. The sequence of the human A3AR contains only one cysteine residue (Cys166) in the second extracellular loop (EL2), which putatively forms a conserved disulfide bridge with the respective cysteine residues of TM3 (Cys83). Homology models of the A3AR have been helpful in providing structural hypotheses for the design of new ligands. Site-directed mutagenesis of the A3AR shows an important role in ligand recognition for specific residues in TM3, TM6 and TM7.