Abstract | Atherosclerosis is a chronic inflammatory disorder that develops in response to hyperlipidaemia. Cells from both the innate and adaptive immune systems contribute to the development of atherosclerotic lesions. The role of natural killer T (NKT) cells in response to microbial pathogens and inflammatory disorders such as atherosclerosis has received increasing attention in the past 10-15 years. Endogenous self-lipid antigens and exogenous lipid antigens, including those on microorganisms can activate NKT cells. CD1d molecules on antigen-presenting cells present these lipids to the T-cell receptor on NKT cells, which results in the rapid production of cytokines and cytotoxic proteins. NKT cells can also be activated in a CD1d-independent manner. Numerous studies have shown that NKT cells can promote atherogenesis. Various NKT cell sublineages have been described, but the participation of each in atherogenesis requires further characterization. In this Review, we provide an overview of NKT cells in the immune system, discuss CD1 molecules and lipid antigen presentation, and describe the interaction of the CD1d-NKT cell network with gut microbiota and its effect in modulating the activity or levels of NKT cells, which might in turn influence atherosclerosis. Although the exact mechanisms by which NKT cells promote atherosclerosis have not been fully elucidated, several potential mechanisms are proposed.