Inflammation is initiated by specific pathogen constituents, in addition to intrinsic host molecules that are released by injured or dying cells. Among such host endogenous pro-inflammatory factors, nucleotides (mainly ATP) are attracting increasing interest for their potential as natural adjuvants. Extracellular ATP stimulates a family of receptors, named P2, one of which, P2X₇, is a potent mediator of interleukin (IL)-1β and IL-18 processing and release. The mechanism and physiological significance of this unusual pro-inflammatory activity have long remained elusive. Recent data unveiling the structure and function of a novel caspase-activating platform, the inflammasome, shed light on P2X₇ receptor coupling to IL-1β release, and suggest a fascinating scenario for the initiation and amplification of the innate immune response. Here, I outline the intriguing links between the P2X₇ receptor and the NALP3 inflammasome, review recent evidence showing that this receptor is a potent activator of this multimolecular platform and discuss implications for pathogen–immune cell interaction and for anti-inflammatory drug development.