The P2X7 receptor is present in a variety of cell types involved in pain, inflammatory processes and neurodegenerative conditions, thus it may be an appealing target for pharmacological intervention. The extensive use of high-throughput screening (HTS) followed by a hit-to-lead (HtL) program, has prompted a number of firms to identify highly selective and metabolically stable small-molecules possessing activity for both the rat and human P2X(7) receptor, which provide a novel therapeutic approach to the treatment of pain as well as neurodegenerative and inflammatory disorders. To describe the current status of and potential for development of P2X(7) receptor-antagonists. A literature review. We describe the recent discoveries of novel P2X(7) receptor-selective antagonists, along with their biological activity and therapeutic potential.