Scleroderma renal crisis (SRC) is an infrequent complication of a rare disease. To date, many aspects of the pathophysiology of SRC are still mysterious. Since SRC biopsies are not frequently encountered in practice, our understanding of the spectrum of histologic changes is derived from a combination of a limited personal experience and data obtained from several relatively small pathologic studies. This book chapter will be devoted to discuss the pathophysiology and the histologic manifestations of SRC and will cover the most important aspects of clinical and laboratory findings as well as treatment of SRC. Systemic sclerosis (SSc) is a chronic systemic autoimmune disease characterized by excess collagen production. According to the extent of cutaneous sclerosis, SSc can be classified as either diffuse cutaneous (dc) or limited cutaneous (lc) variant (Sakkas, 2005). Many studies have been conducted to explore the pathogenesis of SSc. Activation of T-cells, B-cells and macrophages have been described and linked to the development and progression of fibrosis (Sakkas, Chikanza, & Platsoucas, 2006). Activated T-cells, mainly T helper lymphocyte type-2 (TH-2), are associated with increased IL-4 and IL-13 production and collagen accumulation. Activated B-cells produce autoantibodies that can facilitate transformation of fibroblasts into more fibrotic phenotypes while activated macrophages can accumulate in the perivascular spaces to produce transforming growth factor-B and platelet derived growth factor, which can also promote fibrosis. In addition to collagen accumulation, endothelial cell injury appears to play a central role in the pathogenesis of SSc. Increased permeability of the nail fold capillaries (Bollinger, Jager, & Siegenthaler, 1986) and increased endothelial apoptosis (Sgonc et al., 1996)have been described in SSc patients. Endothelial cell injury in SSc may be triggered by anti-endothelial antibody (Worda et al., 2003), cytokines (Kahaleh, 2004), complement abnormalities (Venneker, van den Hoogen, Boerbooms, Bos, & Asghar, 1994) and/or cellular cytotoxicity (Sgonc et al., 2000). Scleroderma renal crisis (SRC) can complicate the course of up to 10-20% of patients with SSc. SRC is most commonly encountered in patients with dcSSc; however, it can still occur in patients with lcSSc(Sugimoto, Sanada, & Kashiwagi, 2008; Sugimoto et al., 2006) and even in patients with no significant dermal sclerosis, termed systemic sclerosis sine scleroderma (ssSSc) (Gonzalez, Schmulbach, & Bastani, 1994). Compared to SSc, much less is known