A prevailing view of receptor and G-protein function in cells includes random collisions between the proteins with a great specificity at the sites of protein-protein interaction. Recent evidence suggests that receptors, G-proteins, and effectors may be less mobile and that these systems are more highly organized than previously appreciated. Several types of evidence suggest that receptors do not have free access to all G-protein with which they are capable of coupling. Also, the specificity of signaling in intact cells appears to be significantly greater than in reconstituted systems. The distribution and mobility of G-proteins in cells are restricted to a surprising degree. Thus, complex interactions of the receptors and G-proteins with their effectors and cell membrane machinery appear to play an important role in their function. A full understanding of G-protein-coupled receptors must include a better description of the organization of these systems in cell membranes. Possible roles for noncoated pits (caveolae) and a novel pleckstrin homology domain need to be examined.