New research on the role of vitamin D in health and disease prompted the Endocrine Society to update its Clinical Practice Guideline on vitamin D. This update ais to establish clinical guidelines for using vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to reduce the risk of disease in individuals who don't have any established indications for vitamin D treatment or 25(OH)D testing. A panel of experts identified 14 clinically relevant questions about vitamin D and 25(OH)D testing for individuals without established indications for vitamin D treatment or 25(OH)D testing. A systematic literature review to identify relevant clinical trials and the GRADE methodology guided the process, which considered patient and physician preferences, costs, resources, acceptability, feasibility, and impact on health equity. The panel suggested empiric vitamin D supplementation for children and adolescents ages 1-18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, pre-term birth, and small-for-gestational-age birth; and for those with prediabetes because of its potential to reduce the risk of progression to diabetes. The panel suggested supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggested against empiric vitamin D supplementation above the current Dietary Reference Intakes to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for low 25(OH)D in the general population, nor those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered. When developing its recommendations, the panel prioritized randomized placebo-controlled trials in general populations (i.e., without an established indication for vitamin D treatment or 25(OH)D testing), evaluating the effects of empiric vitamin D supplementation throughout the lifespan as well as in select conditions (pregnancy and prediabetes). Many limitations in the evidence were identified, including the lack of large trials targeting people with low 25(OH)D levels and the lack of trials designed to determine optimal 25(OH)D levels required for disease prevention.