The article reviews the signaling properties of hyaluronan receptors, focusing on the mechanisms by which hyaluronan activates intracellular signaling cascades. Hyaluronan, a large, high-molecular-weight polymer, has been shown to bind to cells and promote cell motility and protein tyrosine phosphorylation. The study of murine cardiac cells derived from hyaluronan synthase 2 (HAS2) knockout mice has provided strong evidence for the signaling capability of hyaluronan. The review highlights the roles of two key hyaladherins, RHAMM and CD44, in mediating hyaluronan signaling. CD44, an integral protein subject to extensive alternative splicing, interacts with tyrosine kinases (e.g., p185HER2 and c-Src kinase) and Rho-like GTPases (e.g., RhoA and Rac1), regulating cell adhesion, proliferation, migration, and angiogenesis. RHAMM, another alternatively spliced protein, distributes into multiple compartments and can act as a co-receptor for integral membrane proteins, regulating tyrosine and serine/threonine kinases and Ras GTPase. The size of hyaluronan and the cell background also influence signaling responses. Smaller hyaluronan fragments can induce inflammatory gene expression and cell proliferation, suggesting a role in response to injury. The review concludes that hyaluronan signaling involves specific cellular hyaladherins and is influenced by the size and context of the hyaluronan molecule.The article reviews the signaling properties of hyaluronan receptors, focusing on the mechanisms by which hyaluronan activates intracellular signaling cascades. Hyaluronan, a large, high-molecular-weight polymer, has been shown to bind to cells and promote cell motility and protein tyrosine phosphorylation. The study of murine cardiac cells derived from hyaluronan synthase 2 (HAS2) knockout mice has provided strong evidence for the signaling capability of hyaluronan. The review highlights the roles of two key hyaladherins, RHAMM and CD44, in mediating hyaluronan signaling. CD44, an integral protein subject to extensive alternative splicing, interacts with tyrosine kinases (e.g., p185HER2 and c-Src kinase) and Rho-like GTPases (e.g., RhoA and Rac1), regulating cell adhesion, proliferation, migration, and angiogenesis. RHAMM, another alternatively spliced protein, distributes into multiple compartments and can act as a co-receptor for integral membrane proteins, regulating tyrosine and serine/threonine kinases and Ras GTPase. The size of hyaluronan and the cell background also influence signaling responses. Smaller hyaluronan fragments can induce inflammatory gene expression and cell proliferation, suggesting a role in response to injury. The review concludes that hyaluronan signaling involves specific cellular hyaladherins and is influenced by the size and context of the hyaluronan molecule.