Innate immunity relies upon the ability of a few pattern recognition molecules to sense molecular markers. Ficolins are humoral molecules of the innate immune systems which recognize carbohydrate molecules on pathogens, apoptotic and necrotic cells. Three ficolins have been identified in humans: L-ficolin, H-ficolin and M-ficolin (also referred to as ficolin-2, -3 and -1, respectively). They are soluble oligomeric defence proteins with lectin-like activity and they are structurally similar to the human collectins, mannan-binding lectin (MBL) and surfactant protein A and D. Upon recognition of the infectious agent, the ficolins act through two distinct routes: initiate the lectin pathway of complement activation through attached serine proteases (MASPs), and a primitive opsonophagocytosis thus limiting the infection and concurrently orchestrating the subsequent adaptive clonal immune response. Recently a lot of reports showed that dysfunction or abnormal expressions of ficolins may play crucial roles in the pathogenesis of human diseases including: (1) infectious and inflammatory diseases, e.g., recurrent respiratory infections; (2) apoptosis, and autoimmune disease; (3) systemic lupus erythematosus; (4) IgA nephropathy; (5) clinical syndrome of preeclampsia; (6) other diseases associated factor e.g. C-reactive protein. Precise identification of ficolins functions will provide novel insight in the pathogenesis of these diseases and may provide novel innate immune therapeutic options to treat disease progression. This review discusses the structures, functions, and clinical implications of ficolins and summarizes the reports on the roles of ficolins in human diseases.