Hyaluronan (HA) receptors are expressed in a wide variety of different tissues and have long been known to support the critical cellular functions of adhesion and motility, in addition to a range of different physiological and pathological processes, including immunity, inflammation and tumour metastasis. In recent years, LYVE-1, an HA receptor largely but not exclusively restricted to the endothelia of lymphatic capillaries, has been shown to mediate the entry of immune cells through lymphatic endothelial junctions by engaging with their surface HA glycocalyx, itself anchored to the immune cell membrane by the closely related receptor CD44. Although similar to CD44 in primary sequence, LYVE-1 is functionally distinct, with a mutually exclusive pattern of tissue expression and a marked dependence on avidity for engagement with the long chains of HA—achieved primarily through receptor clustering. Here, we review key data that have defined the in vitro and in vivo functions of LYVE-1, including recent high-resolution crystal structures that have revealed its unusual and reversible “sliding” mode of interaction with HA, as distinct from the conventional “sticking” interaction in CD44. Lastly, we consider the emerging functions of LYVE-1 in sites beyond the lymphatics, namely tissue-resident macrophages and the specialised blood vessels of certain organs, and its potential as a therapeutic target.