Nanocrystals (NCs) have emerged as a platform with significant potential for drug delivery to the central nervous system (CNS). They offer considerable advantages, particularly in improving the solubility, bioavailability, and targeting of hydrophobic therapeutics. Composed almost entirely of active pharmaceutical ingredients, NCs provide high drug-loading capacity without the need for additional carriers. Their small size and surface modifications, such as PEGylation and coating targeting ligands, enhance penetration across various physiological barriers like the blood–brain barrier (BBB), making them an attractive option for CNS-targeted therapies. In addition, NCs have the potential for controlled and sustained drug release, which is crucial for managing chronic CNS conditions. This chapter summarises current administration routes for CNS-targeted NCs and examines how biological barriers and disease-mediated alterations affect the precision delivery of drug NCs to the CNS. Additionally, diverse surface modification strategies aimed at enhancing CNS targeting are highlighted. Last but not least, key challenges are outlined, and future perspectives are offered to advance NCs-based therapies in managing CNS disorders.