Scleroderma or systemic sclerosis (SSc) is a complex disease in which the vasculopathy and the activation of the immune system with production of inflammatory mediators lead to dysregulated fibroblast activation. The resulting excessive deposition of collagens and other extracellular matrix proteins ends in fibrosis and organ dysfunction. The cause is unknown, but environmental factors are thought to play a role by triggering abnormal responses in genetically susceptible hosts. The recent past has witnessed important advances in the definition of mechanisms that underlie the persistent activation in fibroblasts of genes involved in uncontrolled fibrosis, a hallmark of SSc. These include the preferential production of type 2 T cell cytokines in target organs, the presence of autoantibodies with fibroblast-activating capacities, the production of vasoconstrictive mediators that impact on fibroblast biosynthetic properties, the transforming growth factor-beta-related metabolic signature, and the presence of altered signaling pathways in fibroblasts. Furthermore, while no animal models recapitulate all the features of SSc, they have been instrumental for assessing the relevance of specific processes to the development of fibrosis. More importantly, some of the research findings are leading to therapies that target altered processes with the potential of changing the prognosis of some dismal aspects of the disease.