Identification of the mechanisms involved in the pathology of nutrient deficiency provides an understanding of nutrient functions, their role in metabolism, and interactions between nutrients. However, evidence has emerged in recent years that low (suboptimal) intakes of micronutrients are associated with an elevated risk of chronic diseases. The description of micronutrient associations with chronic disease as a deficiency disease does not capture the complexity of these relations. It implies a significant oversimplification of this relation and detracts from the need for development of new approaches to this area of study. Epidemiologic study designs are essential for progress in understanding the micronutrient–chronic-disease relations, and these are described. Two areas wherein epidemiological tools could be incorporated into experimental designs have been vitamin D and prostate cancer, and vitamin D and colon cancer. In each case, biomarkers of exposure, intermediary markers, and mechanisms have been identified and could be implemented in new experimental designs. Measures of exposure would be improved by incorporation of measurements of vitamin D status such as serum 25-hydroxyvitamin D measurements. Several intermediary markers are discussed and may be useful in the characterization of responses. Such developments should aid in the interpretation of studies and identify vitamin D, as well as calcium intakes, that will aid in the prevention of prostate and colon cancer.