Classical methods have been recruited to determine the molecular function and the physiological relevance of G-protein-coupled receptors (GPCRs), including ligand-binding and signal transduction studies, pharmacological receptor profiling in tissues and the characterization of transgenic mouse models. Evolutionary data from both sequenced genomes and targeted retrieved orthologs are increasingly used as a source of structural information. Recent success in sequencing and functionally expressing GPCRs from fossils opens the possibility of studying signaling pathways even in extinct species. Therefore, mining evolutionary data provides an additional source for understanding the functional relevance of individual GPCRs, for interpreting naturally occurring receptor mutations in patients and for guiding structural modeling and mutagenesis studies of GPCRs.