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EP4 is a G protein-coupled receptor for prostaglandin E2 (PGE2) that drives the key pathological processes involved in inflammation, immune suppression, and carcinogenesis, making it a promising drug target for treating various human diseases. Pharmacological blockade of EP4 neutralizes the deleterious effects of PGE2 without impairing the biosynthesis of other protective prostaglandins, thus circumventing the dose-limiting gastrointestinal and cardiovascular adverse events associated with effects characteristic of cyclooxygenase inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Since the discovery of EP4 as a drug target, rapid innovation has led to multiple potent and EP4-selective antagonists advancing to clinical trials. This article comprehensively reviews the medicinal chemistry of EP4 antagonists, analyzes the latest clinical advancements, summarizes recent breakthroughs in dual and triple prostanoid receptor antagonists, and critically evaluates future challenges and opportunities, thereby providing valuable insights and guidance for the development of next-generation EP4 antagonists.