In certain circumstances, internalized receptors are able to continue signaling after endocytosis. Whistler et al. discuss how the interaction of heterotrimeric GTP-binding protein (G protein)-coupled receptors with arrestins and their subsequent endocytosis may contribute to activation of the mitogen-activated protein kinase pathway. This perspective delves into the role that scaffolds may play in organizing and specifying downstream signaling events that occur after internalization of G protein-coupled receptors.