The management and definitive treatment of segmental bone defects in the setting of acute trauma, fracture non-union, revision joint arthroplasty, and tumor surgery are challenging clinical problems with no consistently satisfactory solution. Orthopaedic surgeons are developing novel strategies to treat these problems, including three-dimensional (3D) printing combined with growth factors and/or cells. This article reviews the current strategies for management of segmental bone loss in orthopaedic surgery, including graft selection, bone graft substitutes, and operative techniques. Furthermore, we highlight 3D printing as a technology that may serve a major role in the management of segmental defects. The optimization of a 3D-printed scaffold design through printing technique, material selection, and scaffold geometry, as well as biologic additives to enhance bone regeneration and incorporation could change the treatment paradigm for these difficult bone repair problems.