In the context of cryptogenic neurological disease in children, a brain biopsy is considered after less invasive diagnostic investigations are completed and their interpretation within the clinical context remain inconclusive. Hastening the process may be progressive neurological deterioration. Here we provide a step-by-step guide for clinical teams considering a brain biopsy in pediatric patients to provide a histopathological diagnosis in cryptogenic neurological disease. The chapter further guides the neurosurgeon with the equipment, procedures and recommendations vital to the provision of a superficial or deep biopsy.