Radiation almost uniformly promotes autophagy in tumor cells. While radiation-induced autophagy often serves as a protective function in cell culture studies, it is currently uncertain to what extent autophagy might be induced by radiation in human malignancies; it is furthermore unknown whether autophagy induced by radiation can or should be suppressed for therapeutic benefit. Current clinical trials combining chemotherapeutic drugs or radiation therapy with chloroquine or hydroxychloroquine as autophagy inhibitors may be premature without the benefit of stratification to identify patients whose malignancies might be susceptible to autophagy inhibition as a therapeutic strategy. In addition, there are also concerns as to whether chloroquine and hydroxychloroquine, the agents currently in use, have the capacity to suppress autophagy when administered systemically at tolerable doses. Finally, any agent that actually has the appropriate pharmacokinetic profile to function as a systemic autophagy inhibitor may collaterally disrupt the homeostatic function of autophagy in normal cells.