Epidermolysis bullosa (EB) has become recognized as a multisystem disorder that poses a number of pre-, intra-, and postoperative challenges. While anesthesiologists have long appreciated the potential difficult intubation in patients with EB, other systems can be affected by this disorder. Hematologic, cardiac, skeletal, gastrointestinal, nutritional, and metabolic deficiencies are foci of preoperative medical care, in addition to the airway concerns. Therefore, multidisciplinary planning for operative care is imperative. A multinational, interdisciplinary panel of experts assembled in Santiagio, Chile to review the best practices for perioperative care of patients with EB. This paper presents guidelines that represent a synthesis of evidence-based approaches and the expert consensus of this panel and are intended to aid physicians new to caring for patients with EB when operative management is indicated. With proper medical optimization and attention to detail in the operating room, patients with EB can have an uneventful perioperative course.