Cryptococcus neoformans is an opportunistic fungal pathogen that may lead to life-threatening meningoencephalitis and pulmonary infections in immunosuppressed hosts. The lack of an effective fungicidal regimen and the development of antifungal resistant strains suggest that continued investigation is necessary to devise immunotherapeutic strategies and/or drug targets to combat C. neoformans infections. Studies to date involve investigating the host-pathogen interaction of cryptococcal infections through the genetic manipulation of the yeast, as well as the characterization of the host immune response. Macrophage phagocytosis and killing assays have proven to be invaluable tools in evaluating the putative effects of the genetic manipulation of C. neoformans strains on the virulence composite of the yeast. In addition, the assay is used to assess the efficacy of various immunotherapeutic agents (i.e., antibodies and cytokines) to enhance this cell-based antifungal activity. The purpose of this chapter is to provide a brief overview on host immunity to C. neoformans infection and, in addition, describe a protocol for performing macrophage phagocytosis and killing assays with C. neoformans and its mutants.