CD44 exists in three phases: a typical transmembrane receptor, a matrix-associated fragment of the extracellular domain, and as soluble fragments in the fluid phase. Membrane-anchored CD44 can be cleaved by MT1-MMP at the cell surface and is subject to subsequent dual intramembraneous cleavage by presenilin-1. Presenilin-1–dependent processing of CD44 results in the liberation of a cytosolic fragment, CD44-ICD, that can translocate to the nucleus to control gene transcription. Proteolysis of membrane- anchored CD44 results in the release of CD44 preassembled into complexes with matrix components or the release of the ectodomain that then can accumulate as an integral component of the matrix due to association with other matrix components. Alternatively, transmembrane CD44 may be proteolytically released from the cell surface or synthesized de novo in soluble form. The released ectodomain of CD44 can be retained in the ECM by establishing physical associations with other matrix components such as fibronectin, HA, and collagen. Exposure of the cell-associated matrix to exogenous matrix-modifying enzymes, such as chondroitinase, and leukocyte- or bacterial-derived proteinases generated as the result of infection, inflammation, or tumor metastasis can lead to the enhanced release of sCD44 from the matrix and, in the face of high local concentrations of proteinases, the degradation of sCD44.