This chapter reviews the current state of knowledge regarding how Cryptococcus neoformans invades into the central nervous system (CNS). An understanding of the unique characteristics of the blood-brain barrier (BBB) is essential to comprehend the potential mechanisms by which blood-borne microbes, including C. neoformans, transverse it. Brain microvascular endothelial cells (BMECs), which line the capillaries supplying blood to the brain, have unique tight junctions that contribute to the barrier function of the BBB. A major function of the BBB is maintenance of the neural microenvironment by regulating the passage of molecules into and out of the brain. The role of monocytes in CNS invasion by C. neoformans relies first on clinical observations. When occlusion occurs in blood vessels supplying the CNS, invasion into damaged tissue can occur. Additionally, at early time points, invasion of the CNS by C. neoformans did not occur from the surface of the brain via the invasion of the blood vessels supplying the leptomeninges (pia mater and arachnoid). The other cryptococcal virulence factor that has been linked to brain invasion is urease, which is produced by nearly all clinical isolates of C. neoformans. Urease expression contributes to the CNS invasion by enhancing yeast sequestration within cerebral microcapillary beds during hematogenous spread. Meningoencephalitis is the most common and serious clinical manifestation of cryptococcosis. Remarkable progress has been made toward elucidating the means by which C. neoformans gains access into the CNS.