G proteins couple receptors for many hormones to effectors that regulate second messenger metabolism. G protein dysfunction could involve gain or loss of function. For Gs, the G protein that couples receptors to stimulation of cAMP formation, examples of both types have already been defined. Germline loss of function mutations in the Gs(alpha) gene are responsible for a form of inherited hormone resistance termed pseudohypoparathyroidism (Albright hereditary osteodystrophy). Conversely, somatic gain of function mutations cause constitutive stimulation of cAMP, independent of receptor activation, in acromegaly, in hyperfunctional thyroid nodules, and in the McCune-Albright syndrome. Future work is likely to uncover additional disorders caused by defective G proteins with implications for diagnosis and treatment.