Evidence from diverse studies, such as protein design experiments and analysis of the emergence of drug resistance in human immunodeficiency virus 1 (HIV-1), indicates that protein function can be diminished or altered by mutations at positions distant from the classic functional site. Furthermore, results from correlation analysis of the ligand-binding domain of nuclear receptors suggest that mutation events at positions distributed throughout a protein domain may be involved in functional diversification during the evolution of homologous domain families. This review explores potential applications for a protein design procedure based on correlated substitutions.