A review. The ionotropic P2X7 receptor (P2X7R) has become the focus of intense research interest for a no. of reasons:. (i) It is a cation selective ion channel that is modulated by extracellular ATP. Upon stimulation by high concns. of ATP it generates a non-selective membrane pore which is permeable to hydrophilic mols. with mol. wt. up to 900 Da. (ii) Though its physiol. function is yet to be fully understood, there is high P2X7R expression in microglia. Importantly, this implies a pivotal role for the P2X7R in neuro-inflammatory and -degenerative processes. In addn., P2X7R-stimulated release of traditional neurotransmitters in the brain, such as glutamate and GABA, further supports the involvement of P2X7R in neuro-inflammatory and -degenerative processes. P2X7-knockout animals are also found to be resistant to inflammation and neuropathic pain, which suggests that P2X7 antagonists could potentially serve as all-purpose analgesics. Recent advances in the development of P2X7R ligands have resulted in identification of several different classes of P2X7R antagonists, including ATP analogs (oxidized ATP), dyes (Brilliant Blue G), tyrosine derivs. (KN-62 and KN-04), cyclic imides, adamantane and benzamide derivs. A KN-62 related radioligand has also recently been reported for use in receptor binding assays. A more extensive range of potent, selective P2X7R ligands is required for a better understanding of the cascade of cellular processes assocd. with the P2X7R. This article will review P2X7R ligands discovered to date, together with their biol. activity and therapeutic potential.