Cells of the immune system are, most likely, programmed to die unless recruited into an immune response. An active cell death program may also be induced by a variety of soluble and surface signals, many of which have only recently been recognized. The importance of these pathways in maintaining tolerance is highlighted by the development of lupus-like diseases in three different mouse strains that have spontaneous mutations in the Fas/APO-1 receptor or its ligand. The known function of Fas/APO-1 in signalling apoptosis explains the persistence of self reactive cells in lpr mice although it is unclear, at present, whether Fas defects effect both central and peripheral tolerance. Whereas Fas/APO-1 receptor expression appears to be normal in humans with SLE, other defects in the Fas/APO-1 pathway or other key molecules in the cell death survival require further study.