Zinc availability affects the host response to major trauma and infection and is associated with the classic acute phase response. During the acute phase response plasma zinc levels precipitously decline as a result of mobilization of zinc into the intracellular compartment to assist with vital metabolic functions that enable immune defense, tissue repair and recovery. Despite knowing some but not all of the essential roles that zinc plays in host defense, little is known regarding metabolic zinc requirements at the onset of and during the acute phase response in the context of critical illness. Recent evidence suggests that zinc supplementation may have a beneficial role in the critically ill and that zinc deficiency, prior to host insult, may be disadvantageous. In this review, new data on zinc metabolism, its implication in the pathogenesis of critical illness with a focus on sepsis, and its therapeutic effects are summarized.