An infamous hallmark of neurodegenerative diseases is the accumulation of misfolded or unfolded proteins forming inclusions in the brain. The accumulation of these abnormal structures is a mysterious one, given that cells devote significant resources to integrate complementary pathways to ensure proteome integrity and proper protein folding. Aberrantly folded protein species are rapidly targeted for disposal by the ubiquitin-proteasome system (UPS), and even if this should fail, and the species accumulates, the cell can also rely on the lysosome-mediated degradation pathways of autophagy. Despite the many safeguards in place, failure to maintain protein homeostasis commonly occurs during, or preceding, the onset of disease. Over the last decade and a half, studies suggest that the failure of autophagy may explain the disruption in protein homeostasis observed in disease. In this review, we will examine how the highly complex cells of the brain can become vulnerable to failure of aggregate clearance at specific points during the processive pathway of autophagy, contributing to aggregate accumulation in brains with neurodegenerative disease.