Sialic-acid-binding immunoglobulin-like lectins (Siglecs) are members of the Ig superfamily that bind sialic acids in different linkages in a wide variety of glycoconjugates. These membrane receptors are expressed in a highly specific manner, predominantly within the haematopoietic system. The CD33-related Siglecs represent a distinct subgroup that is undergoing rapid evolution. The structural features of CD33-related Siglecs and the frequent presence of conserved cytoplasmic signalling motifs point to roles in regulating leukocyte functions that are important during inflammatory and immune responses. In this review, we summarise ligand binding preferences and describe recent progress in elucidating the functional roles of CD33-related Siglecs in the immune system. We also discuss the potential for targeting novel therapeutics against these surface receptors.