Cross-sectional and prospective data reveals significant dose-wise health-risk reductions with higher vitamin D status, each with proven mechanistic explanations. RCT causality confirmation is sparse but support is emerging with better appreciation of vitamin Ds biology. Confounding factors in vitamin D RCT design include that nutrients are not pharmaceuticals [increases in serum 25(OH)D concentrations and efficacy with supplementation of deficiency are S-shaped, sizeable biological effects being seen along the steep parts of the S but not in repletion or uncorrected deficiency]; self-supplementation; unassessed dietary intake, sun exposure; unknown baseline/achieved Vitamin D status; genetic variation and unchecked compliance. Analyses on initially deficient subjects using Individual Participant Data are revealing significant health benefits within supposedly failed RCTs & RCT meta-analyses [e.g. URTIs fall by 70% and mortality by 25%], suggesting RCTs should supplement deficiency and achieve adequacy. Circulating 25(OH)D concentrations regulate target tissue vitamin D3 formation [not PTH], explaining their consistent associations with health-benefits. Benefit-thresholds vary observationally and in RCTs [e.g. ˜50 nmol/l for bone-health, ˜80 nmol/l for lowering insulin resistance]. Assay data varies widely despite compliance with international quality control schemes and HPLC/TMS assays are higher than immunoassays [by +533 nmol/l]. Thus, harmonization of immunoassay to HPLC/TMS data raises both thresholds and diagnostic cut-offs, requiring internationally agreed rationalization of these parameters. Low fat foods and ageing reduce vitamin D absorption. Other nutrients modulate calcitriols efficacy [e.g., excess vitamin A reduces VDR activation; magnesium deficiency impairs vitamin D activating enzymes; calcium inadequacy reduces calcitriols rapid non-genomic actions] while vitamins D2 and D3 differ biologically]. Genetic variations affect 25(OH)D binding to DBP, VDR activity and efficacy of vitamin D activating enzymes thereby modulating serum 25(OH)D concentrations. Overall, therefore, vitamin D RCTs should aim to allow for these factors to improve their outcome reliability.