G-protein-coupled receptors (GPCRs) are cell-surface receptors exhibiting a key role in cellular signal transduction processes, thus making them pharmacologically highly relevant target proteins. However, the molecular mechanisms driving receptor activation by ligand binding and signal transduction are poorly understood, since as integral membrane proteins, most GPCRs are very challenging for functional and structural studies. The biophysical properties of natural GPCRs, usually required by the cell in only low amounts, support their functionality in the lipid bilayer but are insufficient for high-level recombinant overexpression and stability in detergent solution. Current structural information about GPCRs is thus limited to a subset of GPCRs with either intrinsically favorable or properly improved biophysical behavior. Recently, directed protein evolution techniques for functional expression and detergent stability have been developed to increase the accessibility of GPCRs for functional and structural studies. Directed evolution does not rely on any preconceived notion of what might be limiting biophysical properties. By random mutagenesis combined with a high-throughput screening and selection system, directed protein evolution has the power to efficiently isolate rare phenotypes and thus contribute to the elucidation of the stability-determining factors, in addition to solving the practical problem of creating stable GPCRs. In the current chapter, protocols for generation of genetic diversity within GPCRs and selection are provided and discussed.