Systemic lupus erythematosus (SLE) is a multisystem autoimmune rheumatic disease characterized by the presence of autoantibodies, many of which are directed against antigens of nuclear origin. In the clinical setting, these antibodies are important in the management of patients with SLE, providing information about disease activity, subtype and prognosis. The clearance of apoptotic debris is defective in patients with SLE. This causes the inappropriate persistence of nuclear antigens and thus a breakdown in peripheral tolerance with ensuing autoantibody generation. Patients have a variety of self-directed antibodies, and it is increasingly clear that some, but not all, of these antibodies are directly pathogenic. This review discusses the current hypotheses regarding the features by which antibody pathogenicity may be determined and therefore predicted, as well as the mechanisms by which these autoantibodies cause tissue damage in SLE and in lupus nephritis in particular. Identifying these pathogenic antibodies may well hold the key to the development of new, targeted therapies.