Cryptococcus neoformans has strong tropism for the central nervous system (CNS), causing meningoencephalitis that is fatal without treatment. While several factors are implicated in its ability to cross the blood-brain barrier (BBB), the mechanisms driving CNS entry remain unclear. Mouse models of cryptococcosis, including strains such as C57BL/6 J, A/J, and BALB/c, are well established, with each strain offering distinct advantages and limitations. The infection route also affects outcomes, with inhalation models more closely mimicking natural infection while intravenous models facilitate rapid fungal dissemination to the brain. Inoculum size and fungal strain virulence are critical factors influencing disease severity, as highly virulent strains can cause rapid mortality before the immune response develops. This chapter focuses on the utilization of the intratracheal infection model and includes protocols for survival and fungal burden experiments, which are used to explore key aspects of fungal CNS dissemination, including fungal virulence, and immune responses.