CD44 is a cell surface glycoprotein present on many cell types. Many CD44 isoforms have been identified. All CD44 isoforms utilize identical transmembrane and cytoplasmic domains. The hematopoietic form of CD44 (CD44H) is the major CD44 protein present on normal human lymphocytes and monocytes. One of the ligands for CD44 is hyaluronic acid (HA), a polymer consisting of repeat units of disaccharide; N-acetyl-D-glucosamine and N-acetyl-D-glucuronic acid. Since HA is present ubiquitously in extracellular matrix and in circulation, promiscuous binding of HA to CD44 may have undesirable affect. Similar to other adhesion molecules, binding of HA to cell surface CD44 requires regulation. In this review, we summarized our studies using a human lymphoma cell line, Jurkat. We found that binding of CD44⁺ Jurkat transfectants to HA requires cellular activation. Cellular activation induces the reorganization of the cytoskeleton proteins. Reorganization of cytoskeletal proteins results in clustering of CD44 on the cell surface. Clustering of CD44 on the cell surface is a prerequisite for the homodimerization of CD44. Our studies on Jurkat transfectants and results from other investigators suggest that interactions between CD44 and HA is a dynamic process and requires the participation of different cellular components; depending of the nature of the cell type and/or the nature of the activation signals.