Subtype selective dopamine receptor ligands have long been sought after as therapeutic and/or imaging agents for the treatment and monitoring of neurologic disorders. We report herein on a combined structure- and ligand-based approach to explore the molecular mechanism of the subtype selectivity for a large class of D2-like dopamine receptor ligands (163 ligands in total). Homology models were built for both human D2L and D3 receptors in complex with haloperidol. Other ligands, which included multiple examples of substituted phenylpiperazines, were aligned against the binding conformations of haloperidol, and three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out. The receptor models show that although D2 and D3 share highly similar folds and 3D conformations, the slight sequence differences at their extracellular loop regions result in the binding cavity in D2 being comparably shallower than in D 3, which may explain why some larger ligands bind with greater affinity at D3 compared to D2 receptors. The QSAR models show excellent correlation and high predictive power even when evaluated by the most stringent criteria. They confirm that the origins of subtype selectivity for the ligands arise primarily due to differences in the contours of the two binding sites. The predictive models suggest that while both steric and electrostatic interactions contribute to the compounds' binding affinity, the major contribution arises from hydrophobic interactions, with hydrogen bonding conferring binding specificity. The current work provides clues for the development of more subtype selective dopamine receptor ligands. Furthermore, it demonstrates the possibility of being able to apply similar modeling methods to other subtypes or classes of receptors to study GPCR receptor-ligand interactions at a molecular level.