The limited availability of antifungal drugs makes the treatment of fungal infections problematic. However, the development of novel drugs is slow and very expensive. In recent years, increasing attention has been given to the use of combination therapy to treat fungal infection. The use of a secondary compound that exerts stress on the fungal cell can increase the overall efficacy of treatment. Understanding the response of the fungal cell to an antifungal drug is a necessary first step in selecting possible targets for secondary compounds. To this end, we undertook a study of the proteomic response of the basidiomycetous fungal pathogen Cryptococcus gattii to the antifungal fluconazole. We identified a previously uncharacterised protein (designated HARP) that was 47.5-fold upregulated in a fluconazole tolerant strain (MIC = 64 ug/mL), 7.8 and 3.9 fold upregulated in two strains with intermediate fluconazole sensitivity (32 ug/mL) and uninduced in a fluconazole sensitive strain (16 ug/mL) when the cells were treated with the drug. BLAST analysis of the HARP protein sequence against the NCBI nr database yielded no significant homologues. However, PFAM and DELTA-BLAST searches identified domain homology with the Shwachman-Bodian-Diamond Syndrome domain. In humans and Saccharomyces cerevisae, proteins containing this domain have a wide range of functions including ribosome maturation, telomere capping and response to osmotic stress. Structural modelling of HARP, and comparison to solved structures of known SBDS domain proteins, revealed very similar tertiary structures. This analysis gives us confidence that HARP may be a homologue of the S. cerevisae protein RTC3 that has been shown to have a role in stress response. Deletion studies are currently being conducted in C. gattii strains. Analysis of the role of this protein may lead to insights into more effective treatment of difficult or antifungal tolerant cryptococcal strains.