Mannan-binding lectin (MBL) plays an essential role in the innate immune system, being a first-line defense against a variety of pathogens. As a pattern recognition molecule, MBL binds to specific carbohydrate structures on the surface of bacteria, viruses, fungi, and parasites. This binding activates the lectin complement pathway, resulting in pathogen opsonization, inflammation, and direct lysis. Additionally, MBL stimulates phagocytosis by promoting microbe recognition and uptake by immune cells. Low levels or variant alleles of MBL are associated with enhanced risk of infection, autoimmune diseases, and inflammatory pathologies. In this review, we investigate MBL’s molecular mechanisms and physiological role, as well as its clinical relevance and therapeutic opportunities. Based on updated knowledge on immunology and genetics, we analyze how deficiencies in MBL affect immune responses and diseases. We speculate on the possibility of MBL-based therapies to cure immune-related diseases. Despite MBL’s important role in immunity, we are far from a comprehensive understanding of its interactions in the larger network of innate immunity. Generating therapeutic strategies that boost MBL function in immunocompromised hosts would be of interest.