Apoptotic cells are specifically recognized and rapidly removed by professional phagocytes or neighboring cells by incompletely characterized mechanisms. Apoptotic cells are a potential source of autoantigens and, therefore, their efficient elimination, thus preventing unwanted immune reactions is essential. Accumulating evidence suggests that molecules of the innate immune system, including complement components and pentraxins, have a role in the removal of apoptotic cells. Therefore, it has been postulated that in situations with massive apoptosis, defective removal of apoptotic material, as a result of hampered opsonization by pentraxins and complement, can lead to the development of an autoimmune response. In this Review the potential role of complement and pentraxins in the clearance of apoptotic cells will be discussed.