Many lines of evidence indicate that the key initiating event in early atherosclerosis is the subendothelial retention of cholesterol-rich, atherogenic lipoproteins. Once retained, these lipoproteins provoke a cascade of responses that lead to disease in a previously non-lesional artery. We review recent experimental work that has substantially reinforced this hypothesis. Lipoprotein retention has been shown to be a pivotal requirement in the murine model of atherosclerosis: low-density lipoprotein, engineered through site-directed mutagenesis of apolipoprotein-B100 to bind poorly to arterial proteoglycans, causes relatively few lesions in vivo, even during significant hyperlipidemia. In addition, many molecules in the arterial wall that are involved in the retention of atherogenic lipoproteins and in arterial responses to retained material have recently been characterized. Overall, the response-to-retention hypothesis can now be regarded as a central paradigm in our understanding of the pathogenesis of this deadly disease.