<p>The P2X7 receptor (or P2X7) is an ATP-gated ion channel with important roles in the immune and other body systems. Much has been garnered about P2X7 using the first published anti-human P2X7 monoclonal antibody (mAb) (clone L4). This mAb can be used to impair P2X7 channel and pore activity and events downstream of P2X7 activation in vitro and in vivo. Immunolabelling with this mAb has been used in flow and mass cytometry, confocal microscopy and immunohistochemistry to help establish the presence of P2X7 on human leukocytes and other primary cell types, as well as various malignant cell lines. This mAb has been applied to immunoprecipitate P2X7 to identify co-associated molecules to help uncover novel roles of the receptor such as phagocytosis. Recently, this mAb has been shown to mediate complement-dependent cytotoxicity, offering a new avenue of limiting P2X7-mediated processes by depleting P2X7⁺ cells. Finally, this mAb has been used to identify and characterise polymorphic and other variants of P2X7. This article will discuss the origins and various applications of the anti-P2X7 mAb (clone L4). As an early user of this mAb and pioneer of other purinergic technologies, this article is a tribute to the late Francesco Di Virgilio.</p>