There is growing interest in using nanomaterials as carriers for the delivery of drugs in diseases such as cancers and central nervous system (CNS) disorders. Although several nanomaterial-based products have been approved, the regulatory framework for their use in humans remains limited. Nanomedicines (NMs) are usually not designed to cross the blood-brain barrier (BBB). Given the lack of a comprehensive set of standardized methods to assess their in vivo fate, there is an urgent need to characterize NM biodistribution as well as the toxicity that could result from their interaction with the CNS. Here, we discuss the risks of potential unwanted BBB crossing and brain toxicity of nanocarriers (NCs), along with the safety assessment and current regulatory challenges related to NMs.