This paper presents methods for the rapid manufacturing of replacement bone fragments using a Subtractive Rapid Prototyping process called CNC-RP. The geometry of segmental defects in bone, resulting from traumatic injury or cancerous tumor resection, can be reverse-engineered working from medical images (such as CT scans), and then accurate defect fillers can be automatically generated in advanced synthetic biomaterials and other bioactive/biocompatible materials. The research provides evidence that suitable bone geometries can be created using subtractive RP from a variety of materials including Trabecular Metal® (porous tantalum), polymers, ceramics, and actual bone allografts. The research has implications in the orthopaedic treatment of segmental bone defects, as custom prototyped bone fillers should aid in bone growth and improve recovery.