Vascular endothelial injury in SSc leads to a host of pathological changes in the blood vessels that adversely impact the physiology of many organ systems and eventually results in a state of chronic tissue ischaemia. Current hypotheses in SSc vascular disease pathogenesis suggest a possible infectious or chemical trigger(s) that activates both cellular and humoral immunity. Products of immune activation may lead to vascular injury possibly through the production of autoantibodies and the release of products of activated T cells that can directly damage the endothelium. Knowledge of the initial trigger of immune activation in SSc may offer an opportunity to develop a multiple step strategy for therapeutic intervention.