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Prokinetic medications currently on the market offer only modest symptomatic relief, frequently reaching a plateau in efficacy, and their long-term use is limited by safety concerns, especially those related to cardiovascular and neurological side effects, as well as limited regional availability of some agents. The conceptual framework has moved beyond a purely neurocentric model due to recent advances in our understanding of GI motor physiology. The integrated functions of enteric neurobiology, gut-brain axis signaling, smooth muscle contractile pathways, interstitial cells of Cajal as motility pacemakers, and neuromodulatory circuits are highlighted by emerging mechanistic insights. These advancements have made it easier to find new pharmacologic targets and treatment approaches. An overview of new classes of prokinetic and motility-modulating drugs, such as selective receptor agonists and antagonists, hormone-based treatments, neuromodulators, and drugs that target pacemaker cell and smooth muscle function, is given in this review. 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