Vitamin D(3) affects both the innate as well as adaptive immune responses. Epidemiological studies have established that vitamin D(3) deficiency plays an important role in tuberculosis (TB) and viral influenza prevalence as well as susceptibility to active disease in TB. Vitamin D(3) status has been associated with the clinical course of HIV infection and drug interaction with anti-retroviral therapy. This article reviews the immunomodulatory capacity of vitamin D(3) and examines the impact of vitamin D(3) supplementation as a preventive or therapeutic intervention with the intent to uncover its potential therapeutic application in infectious diseases and to identify novel areas for future research. We present a review of randomized, controlled clinical studies conducted in humans which included assessment of the immune function or clinical outcome as study end points. Current data support vitamin D(3) supplementation as risk-modifying intervention in tuberculosis and viral respiratory tract infection, but the optimal dosage regimen remains to be determined. However, to date the knowledge on its role in fungal infection and sepsis is limited although a potential benefit could be harnessed from its ability to curtail the unrestrained pro-inflammatory response and therefore prevent excessive collateral tissue damage.