IL-1β and IL-18 are crucial mediators of inflammation, and a defective control of their release may cause serious diseases. Yet, the mechanisms regulating IL-1β and IL-18 secretion are partially undefined. Both cytokines are produced as inactive cytoplasmic precursors. Processing to the active form is mediated by caspase-1, which is in turn activated by the multiprotein complex inflammasome. Here, we show that in primary human monocytes microbial components acting on different pathogen-sensing receptors and the danger-associated molecule uric acid are all competent to induce maturation and secretion of IL-1β and IL-18 through a process that involves as a first event the extracellular release of endogenous ATP. ATP release is followed by autocrine stimulation of the purinergic receptors P2X₇. Indeed, antagonists of the P2X₇ receptor (P2X₇R), or treatment with apyrase, prevent IL-1β and IL-18 maturation and secretion triggered by the different stimuli. At variance, blocking P2X₇R activity has no effects on IL-1β secretion by monocytes carrying a mutated inflammasome that does not require exogenous ATP for activation. P2X₇R engagement is followed by K⁺ efflux and activation of phospholipase A₂. Both events are required for processing and secretion induced by all of the stimuli. Thus, stimuli acting on different pathogen-sensing receptors converge on a common pathway where ATP externalization is the first step in the cascade of events leading to inflammasome activation and IL-1β and IL-18 secretion.