Rates of proteolysis are controlled differentially for individual proteins depending on the cell’s physiological and pathological conditions. The proteasome is the converging point in the cell for thousands of ubiquitinated proteins that are generated from hundreds of distinct molecular pathways. As our knowledge of biological processes in the system has grown for the last decades, so have the ties between the system and various human diseases including neurodegenerative diseases. Recently, growing interests are in autophagy, another proteolytic system in the cell. In this presentation, I intend to provide an example of studies which were involved in regulation of proteasome activity through small-molecules, direct delivery of exogenous enzymes, and their structural modification. The overall proteasome activity in the cell appeared to be linked with autophagic flux. These data will demonstrate that manipulation of proteasome and autophagy is possible, tolerable to cell, and potentially beneficial to cells under various stress conditions.