Publisher Summary The overarching purpose of the Women's Health Initiative (WHI) was to evaluate the efficacy and safety of three commonly used preventive health interventions: postmenopausal hormone therapy, low-fat diet, and calcium plus vitamin D supplementation. The trial interventions were potentially beneficial for the majority of postmenopausal women regardless of age. Further, because all major outcomes of the study are more common with aging, it was important to include the older, more susceptible population for greater power in the data analysis. Healthy women aged between 50 to 79 were enrolled. This chapter provides a detailed explanation of the rationale for the study design. Results from the two HT arms are not congruent on all primary end points. The statistically significant beneficial findings in both arms of the hormone trial include the decreased risk of hip fracture, prevention of coronary heart disease, and increased risk of stroke. The WHI Low-Fat Dietary Modification study was designed to test the hypothesis that lowering total fat intake would reduce the risk of breast and colorectal cancer in postmenopausal women. A secondary end point is the effect of low-fat diet on cardiovascular disease. The WHI Observation Trial is comprised of 93,676 women. It is yet another extensive source of biospecimens for the study of disease markers.