A common feature of neurodegenerative diseases is the accumulation of disease-specific, aggregated protein species in the nervous system. Transmissible spongiform encephalopathies are universally fatal neurodegenerative diseases involving the transconformation and aggregation of prion proteins. At the cellular level macroautophagy has been identified as an efficient pathway for the clearance of these toxic protein aggregates. Hence, recent research has focused on the pharmacological manipulation of autophagy as a potential treatment for neurodegenerative diseases. Independent of their effects on the estrogen receptor, tamoxifen and its metabolite 4-hydroxytamoxifen are well known inducers of autophagy. However, we recently reported that the ability of 4-hydroxytamoxifen to clear prion infection is independent of autophagy. In contrast, we provide a model whereby perturbation of cholesterol metabolism, and not autophagy, is the main mechanism whereby 4-hydroxytamoxifen is able to exert its anti-prion effects. Thus, while tamoxifen, a widely available pharmaceutical, may have applications in prion therapy, prions may also represent a special case and may require different pharmacological interventions than other proteinopathies.