Many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease, are associated with the formation of intracellular aggregates by toxic proteins. It is therefore crucial to understand the factors that regulate the steady-state levels of these 'toxins', at both the synthetic and degradation stages. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin–proteasome system and macroautophagy. Dysfunction of the ubiquitin–proteasome or macroautophagy pathways might contribute to the pathology of various neurodegenerative conditions. However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases.