Epidermolysis bullosa (EB) encompasses a wide spectrum of rare genetic disorders in which an abnormality in collagen leads to loss or absence of normal intracellular bridges. Friction or shear forces on the skin and mucosa result in blister, bullae, and scar formation. We present our experience in the management of a patient with EB who required multiple procedures for squamous cell carcinoma of the left arm, including forequarter amputation. We describe the anesthetic challenges in caring for a patient with EB undergoing major orthopedic surgery.