Abstract: Hematopoietic stem cell transplantation (HSCT) and immunosuppressants are widely used for treating patients with hematological malignancy (HM); however, the incidence and mortality of invasive fungal disease (IFD) in these patients are increasing. IFD usually has hidden onset, rapid progress, and difficult diagnosis and thus becomes aserious complication that threatens patients with hematological tumors. Posaconazole, a second-generation triazole antifungal drug with a wide antibacterial spectrum, greatly reduces the incidence of IFD among patients with hematological tumors. Because many factors can affect the absorption, distribution, metabolism, and clearance of posaconazole oral suspension, its blood concentration cannot reach the prevention target; hence, fungal breakthrough infections often occur. Consensus on how to prevent and treat breakthrough IFD after prophylaxis with posaconazole oral suspension is currently lacking. This review intends to summarize the occurrence of and prevention strategies for breakthrough IFD after oral posaconazole suspension prevention.