The toll-like receptors (TLRs) are a class of transmembrane molecules that have important functions in both innate and acquired immunity. As part of the body's normal immune defense against microbial pathogens, stimulation of these receptors will trigger the inflammatory response cascade and the release of cytokines. Activation of these receptors also plays a role in a variety of systemic inflammatory diseases such as asthma, sepsis, atherosclerosis, acute coronary artery disease, and left ventricular remodeling. Pharmacologic approaches to modify the actions of TLRs are now under consideration as potential treatments for inflammatory systemic diseases that include atherosclerosis. At the same time, it is essential to characterize the benefits and risks of modifying such an important part of the body's innate immune system.