This article draws on the literature and practical experience to present a clinical protocol for the prosthetic treatment of surgical patients for whom there is no possibility of temporary or permanent restoration of the lost structures. Localization of the tumor, its stage, and its direction of infiltration affect the margin of resection, and thus determine the functional and esthetic deficiencies. The main purpose of reconstructive treatment is to enable patients who have undergone surgery to return to normal everyday life and presence in the community. Restoration of the facial appearance and of the functions of the stomatognathic system—such as chewing, swallowing, and the ability to speak—helps patients feel psychologically better and has a positive effect on the overall treatment results. Clinical protocol during prosthetic rehabilitation of such patients often requires individual and uncommon solutions which present difficulties even for skilled and experienced clinicians. We here pay special attention to the differences between standard procedures and the clinical protocol for prosthetic treatment of patients with tissue deficiencies in the maxillofacial area. We discuss complications in the surgical approach, including those caused by radiotherapy and chemotherapy. Insufficient prosthetic area with increased resilience, contractive surgical scars, and often uneven muscle function lead to additional difficulties in the rehabilitation of patients after surgery. It is important to remember that oncological patients require constant multidisciplinary care. Cooperation between prosthodontists and oncologists, physiotherapists, psychologists, speech therapists, and other specialists, as needed by the patient’s condition, is of crucial importance.