Iron homeostasis is often disrupted in acute disease with an increase in catalytic free iron leading to the formation of reactive oxygen species and subsequent tissue-specific oxidative damage. This article highlights the potential therapeutic benefit of exogenous hepcidin to prevent and treat iron-induced injury, specifically in the management of infection from enteric gram-negative bacilli or fungi, malaria, sepsis, acute kidney injury, trauma, transfusion, cardiopulmonary bypass surgery, and liver disease.