Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with endocrine diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several diseases with classic hypophenotypes or hyperphenotypes of the target endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology.