Atherosclerosis is a chronic inflammatory response characterized by the accumulation of cells of innate and acquired immune systems within the intima of the arterial wall. Macrophages are the predominant participant in innate immune responses in atherosclerosis. Protein receptors expressed by macrophages and endothelial cells recognize components and products of microorganisms and play a vital role in innate immunity. In particular, the members of the toll-like receptor (TLR) family play a critical role in the inflammatory components of atherosclerosis. Both exogenous ligands involved in microbial recognition as well as endogenous ligands involved in sterile inflammation pathways are implicated in the pathology of atherosclerosis. In this review, we discuss our current understanding of the role of TLRs and their coactivators in atherosclerosis, with particular emphasis on studies in atherosclerosis-prone hypercholesterolemic mice.