Cancer cells can adapt to autophagy inhibition. There are still a number of “black boxes” when it comes to targeting autophagy as a cancer therapeutic. While we know that some cancers are particularly sensitive to autophagy inhibition, the exact biomarkers that dictate autophagy dependence remain at large. It is also unclear if autophagy-independent cells may be exquisitely sensitive to other targeted agents. Recently, it was shown that in autophagy-dependent cancer cell lines that die after acute autophagy inhibition, rare clones can survive by up-regulating NRF2 to maintain protein homeostasis. Consequently, the cells with acquired autophagy independence gained new targetable susceptibilities, i.e., proteasome inhibitors. There are likely additional mechanisms cells can use to circumvent autophagy inhibition and corresponding novel susceptibilities that have yet to be discovered.