Macroautophagy is a cellular degradation mechanism that involves the delivery of cytosolic components (macromolecules or organelles) by the autophagosome to the lysosome for degradation. In mammalian cells, macroautophagy and the ubiquitin proteasome system are 2 major mechanisms to eliminate abnormal proteins accumulated in pathological conditions. Here, the coordination of the 2 pathways to alleviate endoplasmic reticulum stress is reviewed. Also discussed is the regulatory role of macroautophagy and proteasome activity in cell survival and death, as well as the recent discoveries leading to novel strategies of simultaneous control of the proteasome and autophagy activity in anticancer treatment.