Optimal treatment of C gattii in immunocompetent hosts has not been determined. The Infectious Diseases Society of America recently published treatment guidelines for cryptococcal disease. Pulmonary and CNS C neoformans treatment is divided into induction, consolidation, and suppression phases. Induction treatment with amphotericin and flucytosine is usually followed by fluconazole therapy for consolidation and suppression. CNS and disseminated C gattii disease, as well as small isolated pulmonary cryptococcoma, are treated similar to C neoformans with amphotericin, flucytosine, and close radiographic and clinical follow-up. Duration of therapy in isolated invasive disease and isolated pulmonary disease is not well studied, but usual recommendations indicate at least 4 to 6 weeks of amphotericin for severe disease. Although current Infectious Diseases Society of America guidelines address C gattii infection, they do not consider antimicrobial resistance in C gattii. There are several studies indicating that C gattii has high minimum inhibitory concentrations (MICs) to fluconazole; however, true resistance and in vivo susceptibility remain undefined. Treatment of C gattii infection in immunocompetent hosts poses many difficulties, including a robust host immune response, which may include paradoxical worsening of symptoms despite effective antifungal therapy. These patients may have immune reconstitution syndrome, but should also be evaluated for drug resistance and medication adherence issues. Variability in fluconazole susceptibility in C gattii strains, with particularly high MICs measured in the outbreak VGIIa strains from Vancouver Island, complicates treatment as well. Although clear end points to define resistance are not defined, exercise caution if considering fluconazole therapy for severe disease, especially in patients in this endemic region. Treatment of these infections is complicated, but a multidisciplinary approach involving pulmonary, infectious diseases, and neurology specialists can result in good long-term outcomes.