Individuals at highest risk of zinc deficiency (children, elderly, pregnant and lactating women, morbidly ill, alcoholics) have a higher risk of infection. Whereas the essential role of zinc in maintaining adaptive immunity is well recognized, much less is known regarding the innate immune system. We recently reported that zinc deficiency significantly increases mortality in an animal model of sepsis. In particular, zinc-deficient mice had a decreased capacity to clear bacteria and a concomitant increase in NF-kappaB-mediated signaling across multiple vital organs. This occurred in tandem with exaggeration of the acute phase and innate immune response. Strikingly, sepsis patients revealed similar findings in that lower plasma zinc levels were associated with more inflammation and increased severity of illness. Through these investigations we have consistently observed that SLC39 A8 (ZIP8) is unique, relative to other zinc transporters, in that its expression is significantly induced at the onset of infection. Moreover, induction of ZIP8-mediated zinc transport into innate immune cells is vital for proper immune function. Whether ZIP8 functions beyond the conventional role of a zinc transporter remains a work in progress, although new evidence has revealed that ZIP8 expression itself is regulated by NF-kappaB. Taken together, these findings indicate that zinc is vital for proper innate immune function and that hZIP8 is intricately involved in maintaining innate immune defense.