Previous observations raised the possibility that circulating GH-binding protein (GHBP) may serve as a useful index for tissue GH receptor (GHR) responsiveness in humans. Indeed, there are many examples to indicate that across a wide scope of comparative studies, ontogenic data, experimental systems, physiological conditions, nutritional states, and diseases there is a close relationship between the concentration of GHR and the level of serum GHBP. In the present review, we discuss various aspects that might affect differentially cellular GHR and circulating GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism, GHR mRNA splicing, and GH insensitivity (GHI) syndrome patients with normal or high serum GHBP levels. Most previous experimental data were collected through comparative analysis of human GHBP against GHR and GHBP determinations in animal models. Yet, GHBPs possess species-specific properties, and the mechanism for their generation and regulation display evolutionary divergence. Another important aspect is tissue divergence, in terms of GHR regulation and its cleavage to GHBP. Although GHBP is generated mainly from the liver GHR, many other tissues express GHRs and probably also contribute to the total GHBP level. Human GHBP is generated by proteolytic cleavage of GHR at the cell-surface and, thus, occupancy or modulation of GHR turnover/internalization would impact the level of cell-surface GHR that are available for proteolysis. An additional degree of complexity arises from recent reports, implicating a protein kinase C-regulated metalloprotease activity in GHBP generation. This suggests that the proteolytic system, which controls the specific cleavage mechanism and switch between GHR proteolysis and GHBP shedding, is a regulated process. Finally, differential splicing regulation to the full-length, active human GHR (hGHR) and the inactive truncated hGHRtr isoform messenger RNA transcripts might regulate both the production of GHBP and GHR bioactivity, as hGHRtr generates large amounts of GHBP but has a dominant negative effect on GH signaling. Several clinical GH-resistant conditions, such as liver cirrhosis, renal insufficiency, insulin-dependent diabetes mellitus, hypothyroidism, malnutrition, or critical illness are associated with reduced GHBP levels. However, this is not universally true, as in other conditions (e.g. early childhood, acromegaly) decreased GHBP levels are not associated with GHI. Divergence between serum GHBP and insulin-like growth factor I, such as which occur during puberty or obesity, also questions whether GHBP levels reflect GHR function. Even in patients with GHI syndrome, serum GHBP cannot be relied on to detect all GHR mutations. The correct assessment of GHR expression and GH functionality in an individual patient will require, in parallel to measurements of serum GHBP, additional detailed diagnostic screening of the entire GH-insulin-like growth factor I axis.