Invasive Candida and Aspergillus infections are among the most common serious complications occurring in chronically immunosuppressed patients, in particular those with hematological malignancies and transplant recipients. A rational, early systemic antifungal treatment can be based upon imaging diagnostic techniques as well as upon conventional mycological and non-culture-based procedures. The availability of well tolerable and highly efficacious systemic antifungals has improved the spectrum of therapeutic options and the success rates of antifungal treatment. However, with respect to high treatment costs associated with these new agents, it is mandatory to specify indications and limitations for the use of these substances. Voriconazole may well become the new standard primary treatment of invasive aspergillosis. The role of the new echinocandins such as caspofungin, which has recently been approved for salvage treatment of resistant and refractory Aspergillus infections, in primary or combination treatment of invasive aspergillosis must be further studied. Caspofungin is at least as effective as, yet significantly better tolerated than amphotericin B for primary treatment of invasive candidosis in non-neutropenic patients, and has been approved for this indication. The selection of systemic antifungals in patients with invasive Candida infection critically depends upon the identification of Candida species involved, because some non-albicans Candida spp. are resistant to azole antifungals.