Many previous studies have demonstrated that P2X 7 receptors (P2X 7 Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X 7 R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X 7 R and summarize the current knowledge about the putative role of the P2X 7 R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.