C-type lectins (CTLs) form a broad and diverse protein superfamily with the ability to identify a wide array of ligands with their characteristic C-type lectin-like domains (CTLDs), thus governing a broad spectrum of physiological functions. CTLD-containing proteins (CTLDcps) are now classified into 17 groups based on their phylogeny and overall domain organization. While much research has centered on the role of C-type lectins in innate and adaptive antimicrobial immune responses, their significance extends further. They are increasingly acknowledged for their significant involvement in cancer biology. It has been evident that the CLR signaling can wield dual effects akin to a double-edged sword across various microbial or oncogenic scenarios. Consequently, the therapeutic potential of both agonists and antagonists targeting CLR signaling is now surfacing as innovative strategies. The growing body of evidence highlighting the indispensable role of C-type lectin receptors (CTLR) in numerous biological processes underscores the necessity for a deeper comprehension of their functional capabilities in both immune defense and disease contexts.