Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell-linked therapeutic approaches, including immunization and B cell-targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.