The blood brain barrier (BBB) maintains homeostasis by regulating the transport of chemicals at the brain interface. However, it is also one of the largest obstacles for drug delivery to the central nervous system (CNS). The utilization of nanoparticles as drug delivery vehicles is one potential solution to overcome this barrier. This review highlights the characteristics of the BBB that inhibit the passage of drugs to the brain, evaluates the efficiency of current in vitro models to mimic the BBB, and discusses the use of nanoparticles in both in vivo and in vitro models to enhance drug permeability across the barrier. In addition, this review describes factors that influence the passage of nanoparticles (type of polymers and surfactant coating, nanoparticle size) across the barrier. Protein opsonization and phagocytic activity of the reticuloendothelial system limits the amount of drug delivered to the brain, and this article summarizes methods to circumvent these issues. This paper also reviews literature covering opportunities and challenges provided with current applications of nanoparticle drug delivery systems for diseases of the brain, including cancer, HIV, and Alzheimer’s disease.