Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing versus non-relapsing MS immune biology, contributed to our understanding of central nervous system (CNS) immune surveillance, and stimulated new fields of research. Here, we discuss the results of these trials, as well as patient biomaterial-based scientific projects, and how both have informed our understanding of CNS immunopathology.