Atherosclerosis is a chronic inflammatory disease of the arterial wall with (auto)immune component, initiated in response to modified (phospho)lipids. Despite important advances in our understanding of the inflammatory response in atherosclerosis, the critical pathways responsible for the breakdown of immune tolerance to lipoproteins and other self-antigens remain largely unknown. An important feature of ruptured/thrombosed atherosclerotic lesions is the accumulation of apoptotic, and secondary necrotic, lipid-laden macrophages and smooth muscle cells due to defective efferocytosis (clearance of apoptotic cells). This leads to the formation of a large ‘necrotic’ lipid core, associated with enhanced vascular inflammation. Interestingly, defective efferocytosis has been associated with the development of autoimmunity, and patients with systemic lupus erythematosus who show increased accumulation of apoptotic material are at very high risk of accelerated atherosclerosis and myocardial infarction. We hypothesize that accumulation of apoptotic/secondary necrotic cells due to defective efferocytosis, together with modified lipids, activate critical immuno-inflammatory pathways in macrophages and B cells, and break immune tolerance in atherosclerosis and post-myocardial infarction. This is consistent with the critical role played by defective efferocytosis and macrophage activation in atherosclerotic lesion progression, and with our recent unsuspected data showing a critical role for B cell activation in driving lesion development in several models of atherosclerosis. We also propose that interactions between macrophages and B cells are essential for the perpetuation of the pathogenic immuno-inflammatory response in cardiovascular disease. Finally, we will harness this knowledge for a better identification of patients at risk of cardiovascular complications, and will target these pathways to limit the progression and complications of cardiovascular disease.