Obesity is a complex disorder and is a major risk factor associated with the incidence of insulin resistance (IR), diabetes, cardiovascular disease (CVD) and other metabolic disorders. The endocrine paradigm suggests that visceral fat in obesity, consisting primarily of adipocytes, secretes various pro-inflammatory adipokines such as tumor necrosis factor (TNF), leptin, visfatin, resistin, and IL-6 creating a state of local inflammation further resulting in chronic systemic inflammation and accelerating the events leading to systemic IR, diabetes and metabolic syndrome. The insulin-like growth factor (IGF) system plays a major role in growth, development and maintenance of homeostasis in normal cells. IGF binding protein-3 (IGFBP-3), the major binding protein in circulation, has been shown to be associated with obesity, IR, type II diabetes mellitus (T2DM) and CVD. Recent studies have demonstrated the IGFBP-3-specific receptor (IGFBP-3R) is a novel protein mediating the anti-inflammatory function of IGFBP-3. IGFBP-3 inhibits adipokine-induced insulin resistance and early manifestations of atherosclerosis via inhibition of NF-κB signaling in adipocytes. Furthermore, decreases in total IGFBP-3 levels and increases in proteolyzed IGFBP-3 in circulation have been documented in obese populations compared to their normal counterparts further establishing a positive correlation between IGFBP-3 proteolysis and adiposity parameters as well as IR. Conversely, our recent studies have identified that neutrophil serine protease (NSP) PR3, an IGFBP-3 specific protease in obesity, is positively correlated with IGFBP-3 proteolysis, IR, body mass index, TNF and IL-8. These findings strongly suggest that obesity-induced activation of PR3 abrogates the anti-inflammatory, insulin-sensitizing IGFBP-3/IGFBP-3R cascade, resulting in IR and its progression to T2DM. The complete characterization of the underlying mechanism and functional significance of the PR3-IGFBP-3/IGFBP-3R cascade in obesity will foster identification of the diagnostic and therapeutic potential of PR3 inhibition in insulin resistance and its sequelae.