The discovery of the signalling system consisting of receptor activator of nuclear factor-KB ligand (RANKL), its receptor RANKL and its decoy receptor osteoprotegerin (OPG) has been a key step in the understanding of pathophysiology of the bone microenvironment and has provided pharmacological targets for new anti-resorptive drugs. The system is central to the interactions among bone, vascular and immune cells. OPG and a soluble form of RANKL (sRANKL) are present in the blood stream. The measurement of their concentrations offers insights into the regulatory mechanisms of the system and the possibility of using new markers in a number of diseases. Besides bone metabolic disorders, the list includes malignancies, rheumatic and cardiovascular diseases. However, apparent discrepancies in the outcome of studies point to a number of caveats: lack of control of pre-analytical and analytical variables; paucity of data on the metabolic removal of the molecules; the cross sectional design of most studies comparing patients with healthy subjects. Finally, circulating OPG and sRANKL derive from several sources, and their concentrations may be alterated by different coexisting pathological processes. In the absence of tissue-specific isoforms, diagnostic or prognostic significance may be suggested from data obtained in large cohorts, but is still of limited usefulness in single patients.