Cutaneous fibrosis is an integral component of a variety of human disorders including keloids, hypertrophic scar, and most notably, scleroderma. Each has its own etiology and unique clinical characteristics, but all involve the dysregulation of connective tissue metabolism, in particular, the activation of dermal fibroblasts. In this review, we examine various molecular events in scleroderma that may lead to fibroblast activation, and propose a new model to explain the persistence of such activation by scleroderma fibroblasts in the apparent absence of exogenous stimuli.