The Receptor for Advanced Glycation Endproducts (RAGE) is a multi-ligand receptor of the immunoglobulin family. RAGE interacts with structurally different ligands probably through the oligomerization of the receptor on the cell surface. However, the exact mechanism is unknown. Among RAGE ligands are members of the S100 protein family. S100 proteins are small calcium binding proteins with high structural homology. Several members of the family have been shown to interact with RAGE in vitro or in cell-based assays. Interestingly, many RAGE ligands appear to interact with distinct domains of the extracellular portion of RAGE and to trigger various cellular effects. In this review, we summarize the modes of S100 protein–RAGE interaction with regard to their cellular functions.