C-type lectin receptors (CLRs) represent a broad and diversified family of pattern recognition receptors (PRRs) that are mainly expressed on the myeloid cells. They recognize the “non-self” pathogen-associated molecular patterns (PAMPs), or the modified endogenous “damaged self” antigens/the damage-associated molecular patterns (DAMPs) originating from dead cells or of the endogenous “altered self” moieties including the tumor-associated molecular patterns (TAMPs). Upon recognition of specific carbohydrate structures through the carbohydrate recognition domain (CRD), CLRs modulate the immune response by initiation of downstream signaling to generate inflammatory mediators, activation of effector immune cells supporting phagocytosis and antigen presentation, thereby linking innate and adaptive immunity. Moreover, involvement of CLRs in maintaining physiological homeostasis, unfolds a new dimension to their role in cancer. CLRs can eradicate tumor via their interaction with specific tumor antigens, and subsequently activate immune surveillance and promote apoptosis; it can also support tumor growth by modulating angiogenesis and trans-endothelial migration of circulating tumor cells, and provide strategies for tumor escape. Thus, CLR signaling can act like a double-edged sword and therefore, therapeutic roles of agonists or antagonists of CLRs signaling are now being developed as new strategies of cancer immunotherapy. This chapter examines the current understanding of pro-tumorigenic as well as anti-tumorigenic role of CLR signaling.