In principle, two research approaches can be considered for the laboratory diagnosis of transmissible spongiform encephalopathies (TSE): (i) the direct detection of PrPSc and (ii) the detection of surrogate markers in biological materials that show an altered pattern of expression in early stages of the disease or are used in the differential diagnosis of other dementias and thus enable an exclusion diagnosis. This review concentrates on the second approach. It was shown that a single determination of just a few markers (tau-protein, S-100B, 14-3-3-protein) was already sufficient to achieve a high degree of diagnostic certainty in the diagnosis of CJD. On the basis of the available data, it is to be expected that a combination of these markers will bring improved diagnostic strength with regard to the differential diagnosis of dementias as a whole. This especially applies to some of the subtypes of CJD and Alzheimer's dementia (AD).