The growth hormone (GH) receptor is a key regulator of cellular metabolism. Unlike most growth factor receptors, its downregulation is not initiated by its ligand. Like many growth factor receptors, specific molecular mechanisms guarantee that a receptor can signal only once in its lifetime. Three features render the GH receptor unique: (a) an active ubiquitination system is required for both uptake (endocytosis) and degradation in the lysosomes; (b) uptake of the receptor is a continuous process, independent of both GH binding and Jak2 signal transduction; (c) only the cell surface expression of dimerised GH receptors is controlled by the ubiquitin system. This system enables two independent regulatory mechanisms for the endocrinology of the GH/GHR axis: the pulsatile secretion of GH by the pituitary and the GH sensitivity of individual cells of the body by the effects of the ubiquitin system on GH receptor availability.