Glioma is a rare brain tumour with a very poor prognosis and the search for modifiable factors is intense. We reviewed the literature concerning risk factors for glioma obtained in case-control designed epidemiological studies in order to discuss the influence of this methodology on the observed results. When reviewing the association between three exposures, medical radiation, exogenous hormone use and allergy, we critically appraised the evidence from both case-control and cohort studies. For medical radiation and hormone replacement therapy (HRT), questionnaire-based case-control studies appeared to show an inverse association, whereas nested case-control and cohort studies showed no association. For allergies, the inverse association was observed irrespective of study design. We recommend that the questionnaire-based case-control design be placed lower in the hierarchy of studies for establishing cause-and-effect for diseases such as glioma. We suggest that a state-of-the-art case-control study should, as a minimum, be accompanied by extensive validation of the exposure assessment methods and the representativeness of the study sample with regard to the exposures of interest. Otherwise, such studies cannot be regarded as 'hypothesis testing' but only 'hypothesis generating'. We consider that this holds true for all questionnaire-based case-control studies on cancer and other chronic diseases, although perhaps not to the same extent for each exposure-outcome combination.