In the last two decades, knowledge of the neurobiology of prion diseases or transmissible spongiform encephalopathies (TSE) has significantly advanced, but a successful therapy to stop or delay the progression of these disorders remains one of the most challenging goals of biomedical research. Several obstacles to this achievement are in common with other neurodegenerative disorders: difficulties to move from experimental level to clinical stage; appropriate timing of intervention; correct set up of clinical trial. Also in terms of molecular bases of disease, TSE and the other neurodegenerative disorders associated with protein misfolding such as Alzheimer, Parkinson and Huntington diseases, share a central pathogenic role of soluble small aggregates, named oligomers, considered the culprit of neuronal dysfunction: accordingly, these disorders could by termed oligomeropathies. However, the rapid progression of TSE, together with their clinical and molecular heterogeneity, make the therapeutic approach particularly problematic. The main target of the antiprion strategy has been the pathological form of the cellular prion protein (PrP(C)) termed PrP(Sc), invariably associated with the diseases. Several compounds have been found to affect PrP(Sc) formation or enhance its clearance in in vitro models, and prolong survival in experimental animals. However, few of them such as quinacrine and pentosan polysulfate have reached the clinical evaluation; more recently, we have conducted a clinical trial with doxycycline in patients with Creutzfeldt-Jakob disease without satisfactory results. In experimental conditions, active and passive immunization with antibodies against PrP and mucosal vaccination have shown to protect from peripheral infection. Other studies have proposed new potentially effective molecules targeting PrP oligomers. Furthermore, the possibility to interfere with PrP(C) to PrP(Sc) conversion by an active control of PrP(C) is another interesting approach emerging from experimental studies. However, in common with the other oligomeropathies, early diagnosis allowing to treat at risk population in a preclinical stage represent the more realistic perspective for efficient TSE therapy.