In absence of X ray crystal structures of G-protein coupled receptors (GPCRs)-ligand complexes, computer-aided molecular modeling together with site-directed mutagenesis studies become of great importance in order to provide in-silico predictions that facilitate the development of new ligands. In this context, the present review addresses the application of these strategies to the CB(1) and CB(2) cannabinoid receptors. The combination of these complementary approaches represents a tool of considerable value which has allowed to understand the specific ligand-receptor interactions.