Physiological cell death is a process the purpose of which is the elimination of functionally inappropriate cells in a manner that does not elicit an inflammatory response. We have shown previously that the ability of apoptotic corpses to be recognized by macrophages and to modulate the proinflammatory responses of those cells represents paradoxically a gain-of-function acquired during the physiological cell death process. Cells that die pathologically (that is, necrotic vs apoptotic corpses) also are recognized by macrophages but do not down-regulate macrophage inflammatory responses; the recognition of these two classes of native dying cells occurs via distinct and noncompeting mechanisms. We have examined the apoptotic modulation of proinflammatory cytokine gene transcription in macrophages (by real-time RT-PCR analysis) and the corresponding modulation of transcriptional activators (by transcriptional reporter analyses). Our data demonstrate that apoptotic cells target the proinflammatory transcriptional machinery of macrophages with which they interact, without apparent effect on proximal steps of Toll-like receptor signaling. The modulatory activity of the corpse is manifest as an immediate-early inhibition of proinflammatory cytokine gene transcription, and is exerted directly upon binding to the macrophage, independent of subsequent engulfment and soluble factor involvement. Recognition and inflammatory modulation represent key elements of an innate immune response that discriminates live from effete cells, and without regard to self.