Endothelin is a potent vasoconstrictor known to play a role in various painful conditions. This study aims to explore the role of the endothelin system, including its receptors, isoforms, and converting enzymes, in the pathogenesis of cancerous and non-cancerous ailments. Additionally, it evaluates the efficacy of endothelin receptor antagonists in managing pain associated with these conditions. A review of recent studies was conducted to identify the fundamental activities of the endothelin system and the impact of antagonists targeting endothelin receptors on pain relief. The endothelin system has emerged as a crucial player in various painful conditions. Antagonists targeting endothelin receptors have shown promise in alleviating cancer pain, with endothelin secretion observed in cancer cells of diverse histologic types. Moreover, endothelin receptor antagonists have demonstrated potential in managing neuropathic and inflammatory pain syndromes. Therapies targeting the endothelin system, particularly endothelin receptor antagonists, hold significant promise for managing both cancer-related and non-cancer-related pain syndromes, highlighting the therapeutic potential of these agents in pain management.