It is becoming increasingly clear that signaling via G proteincoupled receptors is a diverse phenomenon involving receptor interaction with a variety of signaling partners. Despite this diversity, receptor ligands are commonly classified only according to their ability to modify G protein-dependent signaling. Here we show that 2AR ligands like ICI118551 and propranolol, which are inverse agonists for Gs-stimulated adenylyl cyclase, induce partial agonist responses for the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1͞2 thus behaving as dual efficacy ligands. ERK1͞2 activation by dual efficacy ligands was not affected by ADP-ribosylation of G␣i and could be observed in S49-cyc ؊ cells lacking G␣s indicating that, unlike the conventional agonist isoproterenol, these drugs induce ERK1͞2 activation in a Gs͞i-independent manner. In contrast, this activation was inhibited by a dominant negative mutant of -arrestin and was abolished in mouse embryonic fibroblasts lacking -arrestin 1 and 2. The role of -arrestin was further confirmed by showing that transfection of -arrestin 2 in these knockout cells restored ICI118551 promoted ERK1͞2 activation. ICI118551 and propranolol also promoted -arrestin recruitment to the receptor. Taken together, these observations suggest that -arrestin recruitment is not an exclusive property of agonists, and that ligands classically classified as inverse agonists rely exclusively on -arrestin for their positive signaling activity. This phenomenon is not unique to 2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited -arrestin and stimulated ERK1͞2. These results point to a multistate model of receptor activation in which ligand-specific conformations are capable of differentially activating distinct signaling partners.