Scleroderma [also known as systemic sclerosis (SSc)] is a complex autoimmune disease characterised by pathological remodelling of connective tissues. Although the earliest and most frequent manifestations include blood vessel and immunological abnormalities, the systemic and progressive pathology suggests that fundamental interactions between microvascular damage and inflammation are mechanistically linked to obliterative tissue fibrosis. This review will focus on how model systems have provided clues to these relationships and will discuss new data from the study of novel animal disease models. These reveal how vascular damage and leukocyte accumulation generate the molecular cues that control the profiles of soluble mediators, which regulate the aberrant behaviour of mesenchymal cells within connective tissues, and how the dysregulated expression of these components and their differentiation contribute to the persistent fibrogenic response.