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In 2006, the World Health Organization and the United Nations Children’s Fund released a joint statement advising that, in regions where the prevalence of malaria and other infectious diseases is high, iron and folic acid supplementation should be limited to those who are identified as iron-deficient. Although precipitated, in large part, by a recent report of adverse events associated with iron supplementation in children, questions about the risk/benefit of iron deficiency and mechanisms underlying potential adverse effects of iron in the context of infection are long-standing. Moreover, the implementation of this revised policy is compromised in most settings by the lack of consensus on the best methods to screen for iron deficiency. In response to these concerns a comprehensive review was conducted by a Technical Working Group (TWG), constituted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health, in partnership with the Bill and Melinda Gates Foundation. The review included an evaluation of the putative mechanisms associated with adverse effects of iron in the context of malaria; applicability of available biomarkers for assessing iron status in the context of infections; and evaluation of evidence with regard to the safety and effectiveness of available interventions to prevent iron deficiency, particularly in areas of endemic malaria. The aim of this paper is to summarize the technical details of the larger TWG review conclusion that the occurrence and mechanism(s) of adverse effects associated with providing iron supplements (i. e., pills/liquid) under conditions of malaria and high infection exposure remain a concern, especially in settings where care and treatment are not readily available or accessible. Iron deficiency remains a problem that demands appropriate clinical care. When target groups have already been identified as being iron-deficient, iron supplementation is the intervention of choice for the treatment of anemia and other manifestations of iron deficiency. Of available intervention options to prevent iron deficiency, supplements are probably least desirable, particularly for infants and children. This paper also provides a synopsis of the TWG responses to the recently published Cochrane Review on the safety of iron supplementation for children in the context of malaria, and a research agenda outlined by the TWG that can best address outstanding questions.