Very little is known on the tissue-specific features of proteolytic systems in the body, mainly because we are lacking appropriate techniques to study protein breakdown in different tissues and organs. Experimental evidence has been provided in only skeletal muscle and liver where proteolysis can be studied in incubated muscles or myotubes and hepatocytes, respectively. These data have demonstrated that proteolysis is mainly ubiquitin-proteasome-dependent in skeletal muscle and lysosomal in liver. This led to the assumption that such tissue-specific differences mainly reflect the very different rates of protein turnover in these tissues (ie, slow in muscle and rapid in the liver). Although there is a correlation between the two parameters, our current understanding of proteolysis now shows that the situation is much more complex. In particular, autophagy is not only responsible for proteolysis, but also for the breakdown of any macromolecule. For example, recent data have shown that the breakdown of lipids is tightly connected to energy metabolism in the liver. Several lines of evidence strongly suggest that this might be the case in other tissues and organs, and that our knowledge of the precise role of each proteolytic pathway is far to be understood. This review focuses on some tissue-specific and more general features of proteolysis that are currently contributing to a better understanding of metabolism