Fungi often adapt to environmental stress by altering their size, shape, or rate of cell division. These morphological changes require reorganization of the cell wall, a structural feature external to the cell membrane composed of highly interconnected polysaccharides and glycoproteins. Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes that are typically secreted into the extracellular space to catalyze initial oxidative steps in the degradation of complex biopolymers such as chitin and cellulose. However, their roles in modifying endogenous microbial carbohydrates are poorly characterized. TheCEL1gene in the human fungal pathogen Cryptococcus neoformans(Cn) is predicted by sequence homology to encode an LPMO of the AA9 enzyme family. TheCEL1gene is induced by host physiological pH and temperature, and it is primarily localized to the fungal cell wall. Targeted mutation of theCEL1gene revealed that it is required for the expression of stress response phenotypes, including thermotolerance, cell wall integrity, and efficient cell cycle progression. Accordingly, acel1Δdeletion mutant was avirulent in two models of C. neoformans infection. Therefore, in contrast to LPMO activity in other microorganisms that primarily targets exogenous polysaccharides, these data suggest thatCnCel1 promotes intrinsic fungal cell wall remodeling events required for efficient adaptation to the host environment.