<p>Extracellular adenosine triphosphate (eATP) is a hallmark of inflammatory and tumor-associated microenvironments, where it functions as a key extracellular signalling molecule through activation of purinergic receptors. In the gastrointestinal tract, and particularly in the colon, eATP-mediated signalling regulates epithelial barrier function, neuroimmune interactions, and immune responses. P2X receptors, a family of eATP-gated ion channels, are differentially expressed across epithelial, neuronal, and immune cell populations and are increasingly recognized as contributors to colonic pathophysiology. This review summarizes current evidence on the roles of P2X receptors in inflammatory bowel disease and colon carcinoma, highlighting their involvement in intestinal inflammation, visceral hypersensitivity, immune cell activation, and tumor-associated processes. We discuss how dysregulated P2X receptor signalling contributes to chronic inflammation and supports a tumor-promoting microenvironment, while also emphasizing the context- and cell-type-specific nature of these responses. Finally, we outline emerging therapeutic strategies targeting P2X receptors and underscore the importance of personalized approaches based on receptor expression patterns within the colonic tissue.</p>