Mannose-binding lectin (MBL) has attracted great interest as potential target for passive immunotherapy to prevent or reduce infection in a variety of clinical settings. MBL is a multimeric serum lectin that recognises a broad array of pathogens and initiates complement activation independently of antibody. MBL2, the gene encoding MBL, contains several polymorphisms that influence synthesis, assembly or stability of functional multimeric MBL. Genetically determined MBL deficiency is present in up to 40% of individuals, with up to 8% having profoundly reduced circulating MBL levels. MBL deficiency is usually clinically silent in otherwise healthy individuals, but is associated with the risk and severity of infection when immunity is already compromised. This review provides an overview of the basic biology and genetics of MBL, reviews data regarding MBL disease associations, and discusses the potential clinical utility of MBL replacement therapy.