No specific recommendations exist for the placement or optimal timing of brain biopsies in patients with nonneoplastic neurological disorders. This chapter examines and discusses the diagnostic value, safety profile, and role of brain biopsy in adults with cryptogenic neurological disease. In highly selected patients with cryptogenic neurological diseases, brain biopsy has a high diagnostic yield (>70%) and low incidence of severe complications (<3%). Brain biopsy also appears to be useful in critically ill patients. It is crucial that the indication and feasibility of brain biopsy be carefully evaluated and discussed in a multidisciplinary setting, considering the benefit-risk balance for each individual patient.