As healthcare improves and our ability to support patients with compromised immune systems increases, such patients become more vulnerable to microbes in the environment. These include fungal pathogens such as
Cryptococcus neoformans
, the primary cause of fungal meningitis and a top priority pathogen on the World Health Organization fungal pathogen list. Like many other environmental pathogens,
C. neoformans
must adapt to and thrive in diverse environments in order to cause disease: (i) the environmental niche, (ii) the lungs following inhalation of infectious particles, (iii) the bloodstream and/or lymphatic system during dissemination, and (iv) the central nervous system (CNS), where it causes a deadly cryptococcal meningoencephalitis. Because CNS infection is the driver of mortality and the presenting illness, understanding the dissemination process from both host and fungal perspectives is important for treating these infections. In this review, we discuss the different stages of dissemination, how fungal cells interact with host cells during disease, and the ability to adapt to different environments within hosts.