Atherosclerosis contributes to cardiovascular disease, which is the most common cause of death in the Western World. There is accumulating evidence that inflammation is involved in the pathophysiology of atherosclerosis. The initial host defence against bacterial infection by the innate immune system is essentially executed by Toll-like receptors (TLRs). To date, 10 TLRs have been identified in humans. Among the receptors, TLR-4 has been implicated in LPS signalling, innate immunity and inflammation. TLR-2 is involved in the recognition of Gram-positive bacteria and other components of different pathogens. Using a mouse model and first genotyping analyses, data show that (i) TLR-2 and TLR-4 are expressed in the heart, vasculature and adrenal gland; (ii) bacterial lipids activate MyD88 and NF-kB pathways in these organs; (iii) TLR-2 & TLR-4 deficient mice have an impaired stress response as well as reduced organ/plasma cytokine levels; and (iv) the existence of polymorphisms of the TLR-2 and/or TLR-4 gene can influence patient outcome during cardiovascular disease. This newly recognized role of TLRs in mouse and man during critical illnesses such as inflammation and cardiovascular disease demands a comprehensive analysis of their interactions.