Many orthosteric agonists differentially activate downstream effectors of GPCRs. Such defined induction of signaling has strongly supported the hypothesis termed 'ligand-directed trafficking of receptor signaling' (LDTRS). More recently, subtype-selective GPCR activators, such as allosteric agonists and positive allosteric modulators, have also exhibited the capacity to activate specific signaling pathways. Based on this finding, it may be possible to achieve ligand-specific receptor active states that optimize the biological responses specific to GPCRs. This review discusses recent studies in which both orthosteric and allosteric compounds have been demonstrated to induce LDTRS.