Experimental and clinical data indicate that the initiation and progress of atherosclerosis and its clinical manifestations are first caused by circulating apoB-100 lipoproteins that enter and are retained in the arterial intima. Extracellular sulfated proteoglycans (PGs) of the intima are the retention agents. The PGs also initiate physical and biochemical lipoprotein degradation with the production of bioactive, lipid products that trigger an inflammatory response that leads to atherosclerosis. There are many simple methods for measuring abnormalities of circulating lipoproteins and their relation to atherosclerotic cardiovascular disease (ACVD). However, limited research aims to evaluate procedures that could report quantitatively about the contribution of the interaction of apoB-100 lipoprotein-arterial intima PGs to clinical manifestation of ACVD. In the present review we discuss observations indicating that simple ex vivo evaluation of the affinity of apoB-100 lipoproteins for arterial PGs and glycosaminoglycans (GAGs) can give an indication of its association with clinical manifestations of atherosclerosis. In addition, we discuss molecular and cellular aspects of the apoB-100 lipoproteins association with arterial PGs that are related to atherogenesis and that support the experimental framework behind the current “Response-to-Retention” hypothesis of atherosclerosis.