Mannan‐binding lectin (MBL) is a plasma collectin (C‐type lectin with a collagen‐like domain) and is considered an important component of innate immunity. Circulating MBL is genetically determined for the major part, but plasma concentration is also markedly influenced by nongenetic factors. The carbohydrate‐binding ability of MBL can be inhibited by simple sugars like mannose, fucose and N‐acetylglucosamine, but its greatest avidity appears to be for repeating mannose‐based structural patterns typical of microbial surfaces. By this means, MBL can bind to a wide variety of bacteria and other microbes, neutralizing them and/or opsonizing them by activating complement using the recently discovered lectin pathway of complement activation. Individual humans differ 1000‐fold in MBL concentration, and individuals with low circulating MBL appear to be more vulnerable to infections in a number of clinical settings, especially when combined with secondary immune deficiency. The best evidence that MBL deficiency or insufficiency is physiologically relevant comes from a rapidly expanding literature of clinical studies. MBL insufficiency appears to be a significant risk factor for infections in infants, and for individuals of any age undergoing chemotherapy or post‐transplant immunosuppression. Moreover, MBL appears to have a significant influence on the course of certain chronic diseases like rheumatoid arthritis and cystic fibrosis. Replacement therapy with a plasma‐derived product is safe and seems promising, while recombinant MBL provides hope for large‐scale therapeutic applications. Randomized clinical trials of MBL therapy, which are now on the horizon, should provide unambiguous evidence for the physiological significance of MBL in innate immunity.