The recent discovery that vitamin D regulates expression of the cathelicidin antimicrobial peptide gene has generated renewed interest in using vitamin D to fight infectious diseases. This review describes the historical use of vitamin D or its sources to treat infections, the mechanism of action through which vitamin D mediates its "antibiotic" effects, findings from epidemiological studies associating vitamin D deficiency with increased susceptibility to infection and clinical trials with vitamin D supplementation to treat or prevent infections. Further studies examining an association between vitamin D levels and cathelicidin expression are discussed. The role of cathelcidin throughout the course of infection from the initial encounter of the pathogen to the resolution of tissue damage and inflammation indicates that individuals need to maintain adequate levels of vitamin D for an optimal immune response. In addition, for treating infections, carefully designed randomized, clinical trials that are appropriately powered to detect modest effects, target populations that are severely deficient in vitamin D,and optimized dose, dosing frequency and safety are needed.