In patients suffering from severe traumatic brain injury and massive stroke (hemorrhagic or ischemic), decompressive craniectomy (DC) is a surgical strategy used to reduce intracranial pressure, and to prevent brainstem compromise from subsequent brain edema. In surviving patients, cranioplasty surgery helps to protect brain tissue, and correct the external deformity. The aesthetic outcome of cranioplasty using an asymmetrical implant can negatively influence patients physically and mentally, especially young patients. Advancements in the development of biomaterials have now made three-dimensional (3-D) computer-assisted design/manufacturing (CAD/CAM)-fabricated implants an optimal choice for the repair of skull defects following DC. Here, we summarize the various materials for cranioplasty, including xenogeneic, autogenous, and alloplastic grafts. The processing procedures of the CAD/CAM technique are briefly outlined, and reflected our experiences to reconstruct skull CAD models using commercial software, published previously, to assess aesthetic outcomes of regular 3-D CAD models without contouring elevation or depression. The establishment of a 3-D CAD model ensures a possibility for better aesthetic outcomes of CAM-derived alloplastic implants. Finally, clinical consideration of the CAD algorithms for adjusting contours and their potential application in prospective healthcare are briefly outlined.