Invasive fungal infections, such as invasive aspergillosis (IA) represent a major threat to immunocompromised patients, especially patients with hematological malignancies or who receive hematopoietic stem cell transplantation. Hence, prevention of IA is a critical strategy that requires a clear understanding of the mould's environmental sources and how it is transmitted to immunocompromised patients. Knowledge of the exposure, mechanisms of transmission, and host susceptibility to IA are vital in selecting appropriate preventive strategies to those settings where infection is more likely to occur. Among the strategies to reduce the incidence of IA is the maintenance of high quality air, i.e. air with low spore counts in hospital areas visited by patients at risk. Housing patients in laminar airflow facilities with high-energy particulate air-filtered rooms helps prevent IA, but it is only realistic and cost-effective for the highest-risk groups and for limited time periods. Air filtration is a costly preventive strategy of questionable value when done with portable filtration units. Moreover, air control measures outside the hospital are extremely difficult to implement and this is important since the majority of cases of IA after allogeneic stem cell transplantation occurs during the post-engraftment period. For these reasons, targeted antifungal prophylaxis remains the most promising of the potential prevention strategies against IA. Many older and newer antifungal agents have been used for this purpose. Amphotericin B, being the oldest and most widely used antifungal, has been used prophylactically in various doses and schedules, but has largely been replaced by its lipid and liposomal formulations that have improved safety profile. Although prophylactic fluconazole prevents candidiasis, this drug has no activity against moulds, including Aspergillus spp. On the other hand itraconazole appears to prevent IA in those patients who can tolerate the drug, since its poor tolerability limits its use. The newer extended spectrum triazole posaconazole has been used in prophylactic trials with encouraging results in selected populations of patients at risk. Voriconazole, another extended spectrum triazole that has emerged as the treatment of choice for IA has been used as secondary prophylaxis in immunocompromised patients with history of IA. Echinocandins, such as caspofungin and micafungin appear to be extremely safe and effective for primary and secondary prophylaxis of IA. Patients undergoing transplantation for hematological malignancies from mismatched or unrelated donors are clearly at higher risk of IA compared to patients undergoing autologous transplantation, since among other risk factors they frequently receive moderate doses of corticosteroids for extended periods for Graft vs. Host Disease (GvHD), a well-known risk factor for IA. Hence, results of studies in specific populations should be analyzed with caution and prophylaxis should be applied to similar patients, because antifungals are not devoid of side effects and overuse selects for resistant fungi. In conclusion, more studies are clearly needed to better define patient populations who will clearly benefit from prophylactic antifungal therapy against IA.