Cytosolic alterations of calcium ion concentrations are an integral part of signal transduction. Similar functions have been hypothesized for other metal ions, in particular zinc (Zn 2+), but this still awaits experimental verification. Zn 2+ is important for multiple cellular functions, especially in the immune system. Among other effects, it influences formation and secretion of pro-inflammatory cytokines, including TNF-α. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn 2+ signals. An increase of the intracellular zinc ion concentration occurs upon stimulation of human leukocytes with Escherichia coli, LPS, Pam 3 CSK 4, TNF-α, or insulin, predominantly in monocytes. Chelating this zinc signal with the membrane permeable zinc-specific chelator TPEN (N, N, N′, N′-tetrakis-(2-pyridyl-methyl) ethylenediamine) completely blocks activation of LPS-induced signaling pathways involving p38 MAPK, ERK1/2, and NF-κB, and abrogates the release of proinflammatory cytokines, including TNF-α. This function of Zn 2+ is not limited to monocytes or even the immune system, but seems to be another generalized signaling system based on intracellular fluctuations of metal ion concentrations, acting parallel to Ca 2+.