Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the innate immune response to various microorganisms and other exogenous and endogenous stress factors. Recently, evidence emerged that important inflammatory processes implicit in human atherogenesis are mediated in part via the TLR4/nuclear factor-kappaB pathway. Polymorphisms of TLR4, which attenuate receptor signalling, enhance the risk of acute severe infections but may have opposite effects on atherogenesis. The aim of this review is to critically discuss current experimental and epidemiological evidence for a role of TLR4 in atherogenesis and to highlight the main controversies and perspectives in this emerging field of vascular biology.