Toll-like receptors (TLRs) are germline-encoded receptors that recognize various pathogen-associated molecular patterns (PAMPs). They are key components of the innate immunity which are activated in response to pathogens as well as non-pathogenic components of damaged tissues. TLR agonists have been developed to treat allergies, cancers, and chronic infections by upregulating the innate immune system. TLR antagonists may be used to treat a number of inflammatory conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Recent research also has shown that TLRs are involved in the pathogenesis of atherosclerosis, thrombosis, myocardial remodeling, ischemic/reperfusion injury, and valvular disease. This article reviews the current experimental and clinical evidence for the role of TLRs in the cardiovascular system, and examines the mechanisms by which TLR antagonists could potentially be used in targeted therapy.