SLE is a multifaceted disease; over the past 20 years, as survival has improved dramatically, new challenges have emerged. It is now clear from the results of studies at several centers that SLE is associated with at least a fivefold increased risk of CAD, which is accelerated at its onset and seems to abolish a female premenopausal protection against CAD. Several groups have also found by various techniques that subclinical disease occurs at a frequency of about 35% to 40%. The pathogenesis of atherosclerosis in this context seems to be a complex interaction of factors associated with the disease, its therapy, and traditional risk factors. Indeed, experimental models suggest a synergy of these different dimensions in plaque formation. Hypercholesterolemia has been identified as predictive of both future CAD events and sub-clinical disease. This is mainly the case in those patients in whom hypercholesterolemia is a sustained phenomenon. In addition, SLE itself seems to be a strong risk factor for CAD over and above the effects of the known traditional CAD risk factors. There is a lot that is still unknown about the pathogenesis of CAD in SLE. Current knowledge is sufficient to justify the belief that an aggressive approach to management of traditional CAD risk factors in patients with SLE is likely to have a major impact on morbidity and mortality in this population. For this to happen, patients must be educated about this issue and be encouraged to play an active role in lifestyle modifications. In addition, clinicians who care for patients with SLE need to assume a primary role in screening and coordinating the management of CAD risk factors in these high-risk patients.