Autoimmune diseases result from complex interactions among different T- and B-lymphocyte subpopulations that target a rapidly growing number of autoantigens on different cell types. The etiology of most spontaneous autoimmune disorders, and both the kinetics and hierarchy of the underlying autoimmune responses are poorly understood. However, important advances have been made in recent years in our understanding of how autoreactive lymphocytes cause tissue damage, including the discovery that granzyme B binds to a cell surface receptor on target cells. This review is an attempt to summarize recent developments in this area.