Adipose tissue is considered as an active endocrine organ that releases a large number of adipokines modulating blood pressure, glucose and lipid metabolism, inflammation, and atherosclerosis. Atherosclerosis has been found linked with various traditional and novel risk actors. This chapter describe the updated review of published literature and present research findings describing the linkage of extent and severity of coronary atherosclerosis with two of the adipokines, adiponectin and leptin, as novel risk factors in metabolic syndrome (MetS) patients. A pilot, Case-control study was carried under Sadbhavna Medical and Heart Institute, Patiala and, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, between January to December 2013. MetS patients (n=55) with age ≥18 years, undergoing angiography for diagnosis and/or interventional treatment of atherosclerosis and 25 matched control subjects were recruited. Evaluation of traditional and novel cardiovascular risk factors (adipose-derived hormones) and their association with angiographic-derived presence and degree of atherosclerosis indices (number of blocked vessels, severity index, and extent index) was carried out. Low serum adiponectin and high total cholesterol level were found as the independent predictors of atherosclerosis for number of blocked vessels. For extent and severity index, low adiponectin level was the only significant and independent predictor. Leptin and adiponectin/leptin (A/L) ratio could not prove as significant predictors (p≥0.05). Based on the results, it was concluded that Total cholesterol, adiponectin, leptin and A/L ratio might play a vital pathogenic role not only in the occurrence, but also in the severity, extent, number of vessels blocked complexity in MetS.