The treatment of central nervous system (CNS) disease has long been difficult due to the ineffectiveness of drug delivery across the blood-brain barrier (BBB). This review summarizes important concepts of the BBB in normal versus pathophysiology and how this physical, enzymatic, and efflux barrier provides necessary protection to the CNS during drug delivery, and consequently treatment challenging. Small molecules account for the vast majority of available CNS drugs primarily due to their ability to penetrate the phospholipid membrane of the BBB by passive or carrier-mediated mechanisms. Physiochemical and biological factors relevant for designing small molecules with optimal capabilities for BBB permeability are discussed, as well as the most promising classes of transporters suitable for small-molecule drug delivery. Clinically translatable imaging methodologies for detecting and quantifying drug uptake and targeting in the brain are discussed as a means of further understanding and refining delivery parameters for both drugs and imaging probes in preclinical and clinical domains. This information can be used as a guide to design drugs with preserved drug action and better delivery profiles for improved treatment outcomes over existing therapeutic approaches.