Conventional opioids are widely used for acute pain management in the postoperative setting. However, a primary concern with conventional opioids is their therapeutic window-the range between doses that produce the desired therapeutic effect (analgesia) and doses that produce unwanted opioid-related adverse events (ORAEs). Conventional µ receptor opioids have a narrow therapeutic window in part because of their mechanism of action (MoA): they bind to µ receptors and non-selectively activate two intracellular signaling pathways, leading to analgesia and to ORAEs. This review explores the clinical potential of µ receptor ligands with differential signaling. Agents with a 'differential signaling" MoA represent an innovative approach that may enhance the therapeutic window. These agents modulate µ receptor activity to selectively engage downstream signaling pathways associated with analgesia while limiting activity in downstream signaling pathways that lead to ORAEs. Differential signaling may fulfill an unmet need in the management of postoperative pain.