Tumor progression involves a series of complex interactions between infiltrating malignant cells and adjacent normal tissues. The cell surface receptor CD44 has been implicated as an active participant in a number of these interactions. Although assigned a variety of functions, it is the role of CD44 as a receptor for the glycosaminoglycan hyaluronan that is likely to be of most importance. The matrix macromolecule hyaluronan often becomes deposited in the tissue spaces immediately surrounding invasive tumors. As such, hyaluronan may function as a ligand for CD44-mediated locomotion or assemble into a protective matrix coat surrounding the tumor cells. Alternatively, the adjacent hyaluronan-rich matrices may serve as a barrier to migration, breached in part by aggressive cell types exhibiting a capacity for CD44-mediated hyaluronan endocytosis. The significance of tumor-associated hyaluronan accumulation as well as potential functions of CD44 – hyaluronan interactions are reviewed.