The development of atherosclerosis is the major etiological factor causing cardiovascular disease and constitutes a lipid-induced, chronic inflammatory and autoimmune disease of the large arteries. A long-standing view of the protective role of B cells in atherosclerosis has been challenged by recent studies using B cell depletion in animal models. Whereas complete B cell deficiency increases atherosclerosis, depletion of B2 but not B1 cells reduces atherosclerosis. This has led to a re-evaluation of the multiple potential pathways by which B cells can regulate atherosclerosis, and the apparent opposing roles of B1 and B2 cells. B cells, in addition to having the unique ability to produce antibodies, are now recognized to play a number of important roles in the immune system, including cytokine production and direct regulation of T cell responses. This review summarizes current knowledge on B cell subsets and functions, and how these could distinctly influence atherosclerosis development.