GH has been of significant scientific interest for decades because of its capacity to dramatically change physiological growth parameters. Furthermore, GH interacts with a range of other hormonal pathways and is an established pharmacological agent for which novel therapeutical applications can be foreseen. It is easy to see the requirement for a number of postreceptor mechanisms to regulate and control target tissue sensitivity to this versatile hormone. In recent years, some of the components that take part in the down-regulatory mechanism targeting the activated GH receptor (GHR) have been defined, and the physiological significance of some of these key components has begun to be characterized. Down-regulation of the GHR is achieved through a complex mechanism that involves rapid ubiquitin-dependent endocytosis of the receptor, the action of tyrosine phosphatases, and the degradation by the proteasome. The suppressors of cytokine signaling (SOCS) protein family, particularly SOCS2, plays an important role in regulating GH actions. The aim of this review is to summarize collected knowledge, including very recent findings, regarding the intracellular mechanisms responsible for the GHR signaling down-regulation. Insights into these mechanisms can be of relevance to several aspects of GH research. It can help to understand growth-related disease conditions, to explain GH resistance, and may be used to develop pharmaceuticals that enhance some the beneficial actions of endogenously secreted GH in a tissue-specific manner.