Atherosclerosis is a chronic inflammatory disease characterized by the progressive growth of lesions in the artery wall with activation of both innate and adaptive immunity. Recently, a unique group of immune cells, termed natural killer T (NKT) cells, has emerged as playing a critical role in the regulation of inflammation and immunity. NKT cells share characteristics of conventional T lymphocytes and natural killer cells and express an invariant T cell receptor, which recognizes glycolipid antigen associated with the major histocompatibility complex class I-like molecule CD1d. NKT cells play a role in protection against many autoimmune, inflammatory diseases such as type 1 diabetes, multiple sclerosis and systemic lupus erythematosus. Interestingly, new data is emerging that describes a role for NKT cells in atherosclerosis. Recent studies have shown that CD1d and NKT cells are present in the atherosclerotic lesions of both humans and mice. Furthermore, we and others have demonstrated that absence of CD1d in apolipoprotein E-deficient (apoE-/-) mice ameliorates atherosclerosis and that specific activation of NKT cells is proatherogenic. In addition, hyperlipidemic apoE-/- mice exhibit defective NKT cell numbers and functions. These findings and the well-established role of NKT cells in regulating immunity make these cells attractive targets for immunotherapy of atherosclerosis.