The highly conserved heat-shock proteins (HSPs) from mammals and microbial reagents are among the immunogenic proteins. Their expression is induced in response to a wide variety of physiological and environmental insults. Their functions as molecular chaperones allow cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. Although the role of HSPs in atherosclerosis remains controversial, HSPs were thought to act as autoantigens, and trigger both cell- and antibody-mediated immune responses. However, HSPs possess immunoregulatory attributes as well and therefore, are being exploited for immunomodulation of atherosclerosis either by the adaptive or innate immune system. This review will focus on a number of HSPs from different families including HSPE, HSPB, DNAJ, HSPD, HSPA, HSPC and HSPH. The role of these HSPs, their protective vs. immunogenic properties with special emphasis on their potential as targets to develop therapeutic agent against atherosclerosis will be discussed.