| Summary: | <i>Cryptococcus neoformans</i> (<i>C. neoformans</i>) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain <i>C. neoformans</i> in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, <i>C. neoformans</i> will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, <i>C. neoformans</i> possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and <i>C. neoformans</i> will determine the disease progression. In this review, we describe the current understanding of how <i>C. neoformans</i> migrates to the brain across the blood–brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that <i>C. neoformans</i> uses to modulate host immune responses.
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