The Women's Health Initiative (WHI) was initiated in 1992 as a major disease-prevention research program among postmenopausal women. The program includes a randomized controlled intervention trial involving 68,132 women and four distinct interventions: conjugated equine estrogens, alone or in combination with medroxyprogesterone acetate, for coronary heart disease prevention with breast cancer as an anticipated adverse effect; a low-fat eating pattern for breast and colorectal cancer prevention; and calcium and vitamin D supplementation for hip fracture prevention. Results from this multifaceted trial have made a substantial impact in clinical practice. A companion cohort study among 93,676 women serves as a source for new risk factor information and provides a comparative observational assessment of the clinical trial interventions. A specimen repository and quality-controlled outcome data for a range of diseases are among the resources that support the ongoing research program. WHI clinical trial contributions and challenges are reviewed and discussed.