Hyaluronan is a major macromolecular polysaccharide component of the extra-cellular matrix that confers structural frameworks for cells. Despite its relatively simple chemical composition, hyaluronan mediates many other important functional aspects including signalling activity during embryonic morphogenesis, cellular regeneration and wound healing. Abnormalities in hyaluronan metabolism have been implicated in many diseases, such as inflammatory disorders, cardiovascular diseases and cancer. To date, it has become increasingly clear that hyaluronan production in vertebrates is tightly regulated by three hyaluronan synthases and that hyaluronan catabolism is regulated by an enzymatic degradation reaction involving several hyaluronidases. Together, these discoveries have provided key insights into the physiological roles of hyaluronan and a deeper understanding of the mechanisms underlying altered hyaluronan turnover in diseases. The central aim of this review article is therefore to highlight the multiple roles of hyaluronan in physiological and pathological states via its complex turnover regulation.