Acute lymphoblastic leukemia (ALL) patients comprise a highly immunocompromised group due to factors associated either with the treatment or the disease itself. Invasive mold infections (IMIs) are considered to be responsible for higher morbidity and mortality rates in patients with hematologic malignancies, including ALL. Defining the exact incidence of IMIs in ALL patients has been rather complicated. The available literature data report a highly variable incidence of IMIs, ranging from 2.2% to 15.4%. Although predisposing factors for IMIs in the setting of ALL are ill-defined, retrospective studies have indicated that a longer duration of neutropenia, treatment with high-dose corticosteroids, and a lack of antimold prophylaxis are associated with an increased risk of IMIs. Additionally, the influence of novel ALL treatments on the susceptibility to fungal infections remains obscure; however, initial data suggest that these treatments may induce prolonged neutropenia and thus an increased risk of IMIs. Administering primary antimold prophylaxis in these patients has been challenging since incorporating azole antifungal agents is troublesome, considering the drug-to-drug interactions (DDIs) and increased toxicity that may occur when these agents are coadministered with vincristine, a fundamental component of ALL chemotherapy regimens. Isavuconazole, along with several novel antifungal agents such as rezafungin, olorofim, and manogepix, may be appealing as primary antimold prophylaxis, given their broad-spectrum activity and less severe DDI potential. However, their use in ALL patients needs to be investigated through more clinical trials. In summary, this review outlines the epidemiology of IMI and the use of antifungal prophylaxis in ALL patients.