Acrophialophorais a saprotrophic genus of fungi found in both temperate and tropical regions. The genus is comprised of 16 species, with the subspeciesA. fusisporaandA. levisnecessitating the most clinical concern.Acrophialophorais an opportunistic pathogen with a broad range of clinical manifestations; the fungushas been implicated in cases of fungal keratitis, lung infection, and brain abscess.Acrophialophorainfection 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 ofAcrophialophorainfection. 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 ofAcrophialophorainfection to facilitate an early diagnosis and appropriate interventions.