Heat-shock proteins (HSPs) belong to a group of highly conserved families of proteins expressed by all cells and organisms and their expression may be constitutive or inducible. They are generally considered as protective molecules against different types of stress and have numerous intracellular functions. Secretion or release of HSPs has also been described, and potential roles for extracellular HSPs reported. HSP expression is modulated by different stimuli involved in all steps of atherogenesis including oxidative stress, proteolytic aggression, or inflammation. Also, antibodies to HSPs may be used to monitor the response to different types of stress able to induce changes in HSP levels. In the present review, we will focus on the potential implication of HSPs in atherogenesis and discuss the limitations to the use of HSPs and anti-HSPs as biomarkers of atherothrombosis. HSPs could also be considered as potential therapeutic targets to reinforce vascular defenses and delay or avoid clinical complications associated with atherothrombosis.