The P2X7 receptor is implicated in numerous diseases including pain, neurodegeneration, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis.1 Since the first patents2-4 appeared in 1999, there has been a steady increase in publications describing the identification and optimization of new P2X7 receptor antagonists from a growing list of pharmaceutical companies and academic groups. While no P2X7 receptor antagonists have yet reached the market, two compounds have entered clinical trials (see section 4). Numerous review articles have been published describing the biology, pharmacology, therapeutic potential, and medicinal chemistry of the P2 receptor family in general5,6 and the P2X7 receptor in particular.1,7,8 This Perspective focuses on the study of P2X7 receptor antagonists specifically aimed at the identification and development of drugs. The objective is to provide a comprehensive review of published information in this area from both the patent and journal literature to September 2008. An attempt has been made to group related series of compounds, highlight common issues, and describe the strategies being used to address these problems.