<p>The purinergic P2X7 (P2RX7) receptor is an ATP-gated ion channel expressed in immune and neuronal cells, with central roles in neuroinflammation, neurodegeneration, and synaptic plasticity. It has been implicated in neurodegenerative, psychiatric, neurodevelopmental, epileptic, and tumor-related disorders, as well as age-associated CNS pathologies. Importantly, P2RX7 functions in a context-dependent manner, displaying both neuroprotective and neurotoxic effects. This review summarizes its molecular structure, genetic polymorphisms, and functional mechanisms, while highlighting its therapeutic relevance across CNS diseases. We also discuss the progress and challenges in developing P2RX7 antagonists, emphasizing their clinical potential in modulating neuroimmune pathways and improving CNS therapeutics.</p> Graphical Abstract <p></p>