There are two major routes for clearance of aberrant cellular components: (i) the ubiquitin-proteasomal system (UPS); and (ii) the autophagy pathway. The UPS degrades individual abnormal proteins, whereas the autophagy pathway is the chief route for bulk degradation of large abnormal protein aggregates and aberrant organelles. Impairments of the protein degradation pathways are closely tied with many human diseases. Brain ischemia leads to protein misfolding and aggregation, resulting in overproduction of protein aggregate-associated organelles. Brain ischemia also damages protein degradation pathways. This chapter will discuss molecular mechanisms underlying the impairments of the UPS and autophagy pathways and how such impairments lead to multiple organelle failure and delayed neuronal death after brain ischemia.