Invasive pulmonary aspergillosis (IPA) is a serious opportunistic infection mainly affecting seriously immunocompromised patients. The major risk factor is prolonged granulocytopenia. Most literature on the epidemiology and clinical impact of Aspergillus spp. infections concern patients with hematological malignancies, cancer, stem cell transplantation and solid organ transplant patients. However, evidence from recent literature indicates that Aspergillus spp. may cause invasive disease in other categories of patients without apparent immunodeficiency, including patients in intensive care units (ICUs). Clinical diagnosis of IPA in non-immunocompromised patients is difficult. Standardized diagnostic definitions, developed by the European Organization for the Research and Treatment of Cancer/Mycosis Study Group for research purposes in patients with cancer and in recipients of haematopoietic stem cell transplants, are not feasible for patient categories with an intermediate to low probability for acquiring IPA. In routine clinical practice, most Aspergillus isolates from non-sterile body sites do not represent disease. Invasive diagnostic procedures are often not feasible in patients with severe respiratory insufficiency and critical illness. The presence of systemic risk factors, or underlying predisposing lung disease or general debilitation, may enhance the clinical relevance of a positive culture. The finding of an Aspergillus spp. positive respiratory specimen in an ICU patient should not be discarded; pre-emptive antifungal treatment should be considered, while attempting to substantiate the diagnosis.