Advances in stem therapy, scaffolds, and therapeutic biomolecules are accelerating bone repair research, and model systems are required to test new methods and concepts. The drill hole defect is one such model and is used to study a variety of bone defects and potential therapies designed to repair these injuries. We detail the methodologies required to successfully generate and evaluate drill hole defects. Although performing a successful drill hole defect requires patience and dexterity, investing the time to perfect the technique will provide ample opportunity for the researcher to expand his/her particular research interests. Mastering this technique will allow testing of stem cell therapies, novel scaffold designs, and biomolecules that can be used for clinical translation.