The main obstacle in the treatment of central nervous system diseases is represented by a limited passage of diagnostic and therapeutic agents across the blood-brain barrier, which separates the blood stream from the cerebral parenchyma and maintains the homeostasis of the brain. The growing knowledge about the brain capillary endothelium and the discovery of specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain. Among the different strategies, nanoparticles are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs and thereby disguising their permeation limiting characteristics. Furthermore a surface functionalization of many nanoparticles can easily be achieved allowing the active targeting of nanoparticles to the brain. For this non-invasive approach, the surface functionalization of nanoparticles with biomolecules has shown promising potential for effective drug delivery to the brain. This review indexes the main classes of biomolecules used for the surface functionalization of nanoparticles and discusses their potential as drug delivery systems for an enhanced passage of diagnostic and therapeutic agents into the brain parenchyma.