Acrophialophora is a saprotrophic genus of fungi found in both temperate and tropical regions. The genus is comprised of 16 species, with the subspecies A. fusispora and A. levis necessitating the most clinical concern. Acrophialophora is an opportunistic pathogen with a broad range of clinical manifestations; the fungus has been implicated in cases of fungal keratitis, lung infection, and brain abscess. Acrophialophora infection is particularly of concern for immunocompromised patients, who often present with a more severe disease course involving disseminated infection and may not exhibit typical symptoms. Early diagnosis and therapeutic intervention are critical to the successful clinical management of Acrophialophora infection. Guidelines for antifungal treatment have yet to be established, partially due to the lack of documented cases. Aggressive use of antifungal agents and long-term treatment is required, especially in immunocompromised patients and patients with systemic involvement, due to the potential for morbidity and mortality. In addition to outlining the rarity and epidemiology of the disease, this review provides an overview of the diagnosis and clinical management of Acrophialophora infection to facilitate an early diagnosis and appropriate interventions.