Micronutrient supplementation offers one of the most cost-effective means of improving the health and survival of children in developing countries. However, the effects of supplementation with single micronutrients on diarrhea are not always consistent, and supplementation with multi-micronutrient supplements can have negative effects. These inconsistencies may result from the failure to consider the diverse etiological agents that cause diarrhea and the unique effects each micronutrient has on the immune response to each of these agents. This review examines the separate effects that supplementation with the B-complex vitamins, vitamin C, vitamin E, selenium, and iron have on diarrheal disease-related outcomes. Supplementation with iron may increase the risk of infection by invasive diarrheal pathogens, while supplementation with the remaining micronutrients may reduce this risk. These differences may be due to distinct regulatory effects each micronutrient has on the pathogen-specific immune response, as well as on the virulence of specific pathogens. The findings of these studies suggest that micronutrient supplementation of children must take into account the pathogens prevalent within communities as reflected by their diarrheal disease burdens. The effectiveness of combining multiple micronutrients into one supplement must also be reconsidered.