Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5-positive B lymphocytes in the blood and lymphoid organs. Despite major advances in treatment regimens, this malignancy remains incurable. The emergence of resistance to chemotherapy is a major reason for the treatment failure and relapse. Tumor cells can escape death through activation of autophagy, an important obstacle for successful anticancer therapy. On the other hand, induction of autophagy by anticancer agents may in some instances promote cell death. In this chapter, we review the role of autophagy in CLL and the modulation of this process by genetic manipulation and pharmacological agents, and its outcome regarding cell viability. In particular, we analyze the major factors that determine the level of basal autophagy and provide evidence that this process is active in CLL. We, then, discuss the current knowledge about the regulation of autophagy in CLL, showing the potential clinical interest of histone deacetylase inhibitors.