A number of pathogenic microbes including neuroinvasive viruses, bacteria and parasites are capable of entry into the central nervous system (CNS) and cause a variety of clinical manifestations. The cellular and molecular mechanisms for the CNS invasion have been extensively studied in the last two decades. Viruses invade neurons and thereby cause encephalitis or peripheral neuritis, while bacteria enter the cerebrospinal fluid (CSF) and cause meningitis. In contrast, the mechanisms for parasitic neuroinvasion are much more complex and less clear. The capabilities that enable these elite subsets of pathogens to engineer uptake into the CNS will be the subject of this review.