Atherosclerosis is an inflammatory disease of the arterial wall that carries an important socio-economic burden. The available data strongly suggest that both innate and adaptive immuno-inflammatory mechanisms are the major determinants of plaque complications (called instability). Therefore, most of the important advances in the comprehension of the mechanisms of atherosclerosis came from studies that aimed at the elucidation of the critical components involved in the modulation of the immuno-inflammatory response in experimental models of atherosclerosis. As the T helper (Th)1-driven immune response has been consistently shown to promote atherosclerosis, the general belief is that immunomodulation through Th2 may be suitable to halt the disease process. Here, a novel view of the immuno-inflammatory response in atherosclerosis is presented, in which the natural and/or adaptive regulatory responses modulate both Th1 and Th2 responses, and play a central role in counteracting disease initiation and progression.