GPCRs are revealing more and more complexity as new data about their structure and functionality is obtained. These receptors have the potential to group into dimers and higher oligomers and to signal through several pathways. Currently, signaling pathways include not only those regulated by G proteins but also recently discovered ones involving other accessory proteins. This review summarizes the use of mathematical models for the analysis of pharmacological response from early models assuming monomeric, single pathway receptors to current models proposing oligomeric, multiple pathway receptors. Following a mechanistic approach, the modeling provides insights on the functional features that dimerization confers on receptors and suggests a proposal for drug design based on bivalent ligands and dimeric receptors with multiple signaling pathways.