Despite recent etiopathogenetic advances, systemic sclerosis continues to be one of the most complex systemic autoimmune disease in terms of its therapeutic management. There is no drug tested for any autoimmune disease that has not also been tested for systemic sclerosis, but none have proven effective. Substantial changes have occurred in the last decade, however, with the appearance of new therapeutic targets and the consequent development of highly selective drugs, some of which, such as endothelin antagonists, are now widely used and others, such as tyrosine kinase inhibitors, in which much hope has been placed. There is also increasing interest in evaluating drugs that are capable of blocking fibrotic processes mediated by transforming growth factor beta, which are currently used in nonautoimmune diseases (such as antidiabetic drugs or statins). Unfortunately, recent trials on these new molecules have produced negative results. Increasing research into disease-specific therapies targeting distinct biological pathways should continue. In the future, it is hoped that the simultaneous or sequential use of different drugs will provide better results than currently available monotherapies in patients with systemic sclerosis.