| Summary: | The human pathogenic fungus <i>Cryptococcus neoformans</i> is a global health concern. Previous research in the field has focused on studies using reference strains to identify virulence factors, generate mutant libraries, define genomic structures, and perform functional studies. In this review, we discuss the benefits and drawbacks of using reference strains to study <i>C. neoformans</i>, describe how the study of clinical isolates has expanded our understanding of pathogenesis, and highlight how studies using clinical isolates can further develop our understanding of the host–pathogen interaction during <i>C. neoformans</i> infection.
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