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As a key component of the complement system, mannose-binding lectin (MBL) is one of the linchpins of innate immunity. It is, therefore, not surprising thatMBL2genetic variants affecting the quantity and activity of the MBL protein in serum have been associated with increased susceptibility to infection and autoimmune diseases, and with poorer prognostic outcomes. This enhanced risk is particularly the case for children and immunosuppressed patients, especially when immunity is further compromised by coexistent primary or secondary immune deficiencies. In several disease areas, such as sepsis, cystic fibrosis, and recurrent childhood infections, the association between low MBL-producing allelic variants and disease risk and/or severity is particularly strong. It is here that the use of MBL testing and replacement therapy has reached the threshold of personalized medicine. The role of MBL in health and disease, advances in MBL testing methodologies and key areas for possible applications of MBL replacement therapy are reviewed.