Hyaluronan is an apparently simple polysaccharide that is responsible for tissue hydration but also stimulates cell proliferation, migration, and differentiation via binding to cell surface receptors, such as CD44. The amounts of hyaluronan increase during inflammation and tumorigenesis through the action of chemokines and growth factors. This review discusses some of the evidence that hyaluronan-CD44 complexes trigger signaling cascades that modulate inflammation and tumor progression.