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Neuroanatomical barriers with physical, chemical, and immunological properties play an essential role in preventing the spread of peripheral infections into the CNS. A failure to contain pathogens within these barriers can result in very serious CNS diseases. CNS barriers are inhabited by an elaborate conglomerate of innate and adaptive immune cells that are highly responsive to environmental challenges. The CNS and its barriers can also be protected by memory T and B cells elicited by prior infection or vaccination. Here, we discuss the different CNS barriers from a developmental, anatomical, and immunological standpoint and summarize our current understanding of how memory cells protect the CNS compartment. We then discuss a contemporary challenge to CNS-barrier system (SARS-CoV-2 infection) and highlight approaches to promote immunological protection of the CNS via vaccination. Neuroanatomical barriers are defended by the immune system to safeguard the CNS parenchyma from pathogens. Ampie and McGavern review the anatomy and development of CNS barriers as well as their immunological composition during steady state and in response to infections. They also explore how to protect these barriers via vaccination and then discuss the immunology and neuropathogenesis of a contemporary CNS challenge (i.e., SARS-CoV-2). [ABSTRACT FROM AUTHOR]