C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for a platelet-activating snake venom, rhodocytin. CLEC-2 elicits powerful platelet activation signals in a manner dependent on Src, Syk kinases, and phospholipase Cγ2, similar to the collagen receptor glycoprotein (GP) VI/FcRγ-chain complex. In contrast to GPVI/FcRγ, which initiates platelet activation through tandem YxxL motifs called the immunoreceptor tyrosine-based activation motif (ITAM), CLEC-2 signals via a single YxxL motif called hemi-ITAM. An endogenous ligand of CLEC-2 has been identified as podoplanin, which is expressed on the surface of tumor cells and facilitates tumor metastasis by inducing platelet activation. CLEC-2 in platelets facilitates blood/lymphatic vessel separation by binding to podoplanin in lymphatic endothelial cells during development. In adults, platelet CLEC-2 prevents the backflow of blood into lymphatic vessels at the lymphovenous junction by forming thrombi. Moreover, platelet CLEC-2 maintains the integrity of high endothelial venules in lymph nodes by binding to podoplanin on stromal cells and in hyper-permeabilized capillaries during inflammation. In concert with GPVI, platelet CLEC-2 plays a role in thrombosis and hemostasis, although the precise mechanism remains unknown. Although CLEC-2 expression is almost specific to platelets/megakaryocytes in humans, CLEC-2 is also expressed in dendritic cells in mice, where it plays an important role in adaptive immunity. CLEC-2 may be a good target for a novel antiplatelet drug or antimetastatic drug, which could prevent arterial thrombosis and cancer metastasis, the main causes of death in developed countries. In this article, we review the signal transduction, structure, expression, and function of CLEC-2.