Advancements in early diagnosis and the introduction of effective agents have improved the rates of response of aspergillosis to primary antifungal therapy. These changes allow the subsequent continuation of cytotoxic chemotherapy and/or performance of hematopoietic stem cell transplantation in an increasing number of patients with hematological malignancies. These developments have increased interest in secondary prophylaxis of aspergillosis, because the resumption of myelotoxic chemotherapy in these patients is associated with high rates of relapse of this opportunistic mycosis in the absence of prophylaxis. However, the risk factors for relapsing invasive aspergillosis and the strategies for reducing risk are not well defined. Furthermore, differentiating aspergillosis relapse from reinfection with a new Aspergillus isolate is problematic when using the available laboratory tools. We summarize the existing knowledge regarding the pathogenesis of, risk factors for, and natural history of relapsing invasive aspergillosis and review the limited data regarding the role of secondary antifungal prophylaxis.