Carbohydrate structures on the cell surface encode complex information that through specific recognition by carbohydrate‐binding proteins (lectins), modulates interactions between cells, cells and the extracellular matrix, or mediates recognition of potential microbial pathogens. Galectins are a family of β‐galactoside‐binding lectins characterized by a unique sequence motif in the carbohydrate recognition domain, and evolutionary and structural conservation from fungi to invertebrates and vertebrates, including mammals. Since their discovery in the 1970s, their biological roles, initially understood as limited to recognition of endogenous (“self”) carbohydrate ligands in embryogenesis and early development, dramatically expanded in later years by the discovery of their roles in tissue repair, cancer, adipogenesis, and regulation of immune homeostasis. In recent years, however, evidence has also accumulated to support the notion that galectins can bind (“non‐self”) glycans on the surface of potentially pathogenic microbes, and function as recognition and effector factors in innate immunity. Thus, this evidence has established a new paradigm by which galectins can function not only as pattern recognition receptors but also as effector factors, by binding to the microbial surface and inhibiting adhesion and/or entry into the host cell, directly killing the potential pathogen by disrupting its surface structures, or functioning as opsonins, by promoting phagocytosis and pathogen clearance from circulation. Strikingly, some viruses (HIV, Nipah, IHNV), bacteria (Chlamydia, Streptococcus), and protistan parasites (Trichomonas, Leishmania, Perkinsus) have the capacity to take advantage of the aforementioned recognition roles of the vector/host galectins, for successful attachment or invasion. The recent findings mentioned above have not only revealed an extraordinary functional diversification in this otherwise structurally conserved lectin family, but also suggest unique evolutionary adaptations of the surface glycome of some microorganisms to use host recognition for cell surface adhesion and infection. Thus, it is proposed that galectin‐mediated innate immune recognition and effector mechanisms, which throughout evolution have remained effective for preventing or fighting viral, bacterial and parasitic infection, have been “subverted” by certain pathogens to gain entry into the host.Support or Funding InformationSupported by grant 5R01GM070589 from the National Institutes of Health, and grants IOS‐0822257 and IOS‐1063729 from the National Science FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.