The immune system must be tightly regulated to prevent unwanted tissue damage caused by exaggerated immune and inflammatory reactions. Inhibitory and activating immune receptors play a crucial role in this function via phosphotyrosine-dependent signaling pathways. A significant body of evidence has accumulated suggesting that the siglec family of sialic acid binding Ig-like lectins makes an important contribution to this immunoregulation. The CD33-related siglecs are a distinct subset of inhibitory and activating receptors, expressed primarily on leukocytes in a cell type-specific manner. Here, we critically assess the in vitro and in vivo evidence on the functional role for CD33-related siglecs in modulation of inflammatory and immune responses.