Cardiovascular disease remains a leading cause of mortality in the United States despite the use of new pharmacologic therapy, lifestyle modifications, and different coronary interventions. Atherosclerosis represents a wide variety of pathologic lesions with different clinical impacts. In this review, we address the current understanding of the pathophysiological mechanisms underlying the development of atherosclerosis. We define atherosclerosis as a multifactorial process representing a series of molecular and cellular mechanisms and involving multiple interactions between lipid metabolism, monocyte activation, endothelial cells, cytokines and/or other intracellular metabolic pathways. We also imply that control of atherosclerosis could be achieved through therapeutic interventions at different sites of the inflammatory process. Therapeutic targets could include cytokine pathways, growth factors, transcription factors, defective genes and other intracellular metabolic pathways.