Programmed cell death (PCD) is a key process in the regulation of immune cell development and peripheral immune homeostasis. Caspase-dependent apoptosis, as well as a number of alternative cell death mechanisms, account for immune cell PCD induced by cell-intrinsic and extrinsic pathways. In animal models, compelling evidence has emerged that genetic defects in PCD can result in autoimmune disease. Autoimmune disease can arise from single-gene mutations that affect PCD, and defective PCD has been observed in some tissues and cells from patients with rheumatic disease. Selectively inducing PCD in autoreactive B and T cells is very attractive as a therapeutic strategy because it offers the possibility of permanent elimination of these pathogenic cell subsets. In addition, the anti-inflammatory effects of apoptotic cells may add to the therapeutic benefit of induced PCD. Immune cell subsets vary widely in their sensitivity to specific inducers of cell death, and understanding these differences is key to predicting the outcome of inducing apoptosis for therapeutic means. Here, we review approaches that have been used to induce PCD in the treatment of autoimmune disease, and describe the prospects of bringing these experimental strategies into clinical practice.