Exposure of cells to agonists of receptors linked to G proteins can result in downregulation of cellular levels or redistribution of G proteins from membranes to the cytosol. Agonist-induced reductions in G protein levels have been observed for members of each of the Gs, Gi and Gq families of G proteins, are likely to be dependent upon the level of receptor expression, and are generally restricted to the G protein(s) with which the receptor interacts. The mechanisms responsible, reviewed here by Graeme Milligan, vary with cell type and include both second messenger-dependent and -independent enhanced protein degradation. Agonist-induced reduction in cellular G protein levels can provide one mechanism for the development of sustained heterologous desensitization.