Cellular function and adaptive behavior is often driven by signals generated in response to the local tissue microenvironment. Cell surface receptors that detect changes in extracellular matrix composition and modifications to extracellular matrix components, are ideally positioned to provide highly responsive sensors of changes in the microenvironment and mediate changes in cellular function required to maintain tissue integrity. Receptors can act as "on/off" switches, but ligand/receptor complexes that provide "rheostatic" control may be more sensitive, provide a more rapid mechanism of control and allow for fine-tuning of cellular responses to the microenvironment. Herein, we review evidence that transitions in the physiochemical properties of the extracellular glycosaminoglycan hyaluronan and in the function of its major receptor, CD44, differentially regulate ERK and Rac signal transduction pathways to provide critical rheostatic control of mesenchymal cell proliferation.