Calcitriol induces multiple innate antimicrobial effector mechanisms in vitro, and vitamin D deficiency has consistently been shown to associate with increased susceptibility to diverse respiratory infections in multiple settings. Early randomised controlled trials (RCTs) of vitamin D for prevention and treatment of tuberculosis (TB) and acute respiratory infections (ARI) yielded many positive findings. However, as the field has matured, larger RCTs of vitamin D supplementation have yielded many null results for these outcomes. In this talk I will present updated results from meta-analyses of RCTs of vitamin D to prevent and treat TB, ARI and their complications, incorporating data from recent ‘mega-trials’ (n>5,000) conducted in the US, Mongolia, Australia and New Zealand. I will then reflect on potential reasons for the ‘disconnect’ between predominantly positive findings from laboratory studies, observational epidemiology and smaller clinical trials vs. largely null results for respiratory infection outcomes from Phase III RCTs.