Frame-based stereotactic biopsy is a well-established minimal invasive tool to obtain tissue of intracranial lesions providing a high diagnostic yield, precise accuracy, and a minimal complication rate. Nondiagnostic or inconclusive histopathological results are rare but require standardized diagnostic and therapeutic algorithms. Here, we summarize the predictive factors mentioned in the literature to increase diagnostic yield as well as diagnostic accuracy and recommend management options for patients with nondiagnostic or inconclusive histopathological diagnosis.