Invasive mould infections (IMIs), which are mostly caused byAspergillus spp.andMucormycetes, are opportunistic infections that impose a substantial threat to patients who are considered to be ‘fragile’. There is no fixed definition for fragile patients; however, patients with cancer or acquired immunodeficiency syndrome (AIDS), patients who have undergone organ transplants, and patients being treated in the intensive care units (ICUs) were considered fragile. Management of IMIs in fragile patients is challenging, owing to their compromised immune status. The diagnostic challenges associated with IMIs due to insufficient sensitivity and specificity of the current diagnostic tests lead to delayed treatment. A widening demographic of at-risk patients and a broadening spectrum of pathogenic fungi have added to the challenges to ascertain a definite diagnosis. A recent surge of mucormycosis associated with SARS-CoV-2 infections and the resultant steroid usage has been reported. Liposomal amphotericin B (L-AmB) is the mainstay for treating mucormycosis while voriconazole has displaced amphotericin B as the mainstay for treatingAspergillusinfection due to its better response, improved survival, and fewer severe side effects. The selection of antifungal treatment has to be subjected to more scrutiny in fragile patients owing to their comorbidities, organ impairment, and multiple ongoing treatment modalities. Isavuconazole has been documented to have a better safety profile, stable pharmacokinetics, fewer drug-drug interactions, and a broad spectrum of coverage. Isavuconazole has thus found its place in the recommendations and can be considered a suitable option for treating fragile patients with IMIs. In this review, the authors have critically appraised the challenges in ascertaining an accurate diagnosis and current management considerations and suggested an evidence-based approach to managing IMIs in fragile patients.