Atherosclerosis, a chronic inflammatory disease of the vascular system, presents significant challenges to developing effective molecular diagnostics and novel therapies. A systems biology approach integrating data from large-scale measurements (e.g. transcriptomics, proteomics and genomics) is successfully contributing to deciphering regulatory networks underlying the response of many different cellular systems to perturbations. In this study we have used novel systems biology tools to analyze the pathogenic process of macrophage foam cell formation when exposed to oxidized low density lipoprotein (oxLDL). Our network-driven integrative analysis not only identified the pathogenic network behind atherogenic process but also found the multi layer relationship behind macrophage foam cell formation.