CD44 and RHAMM are two extracellar matrix receptors whose principle ligand is the polysaccharide hyaluronan (HA). Both proteins are involved in wound repair and their aberrant regulation contributes to a variety of diseases including arthritis and cancer. Over the past decade, a number of peptide-based therapeutics that block the binding of CD44 or RHAMM-specific ligands have been developed and tested in experimental models of disease. Here, we review the structure of each of these proteins, the functions they control and the mechanisms, including their interactions with each other, responsible for these functions. We also review the development of peptide mimics that block the key functions of CD44 and RHAMM and their use in experimental models of disease.