Autophagy is a lysosome-dependent mechanism of intracellular degradation for maintaining cellular homeostasis. Dysregulation of autophagy has been verified to be closely linked to a number of human diseases. Consequently, targeting autophagy has been highlighted as a novel therapeutic strategy for clinical utility. Mounting efforts have been done in recent years to elucidate the mechanisms of autophagy regulation and to identify potential modulators of autophagy. However, most of the compounds target complex and multifaceted pathway and proteins, which may limit the evaluation of therapeutic value and in depth studies as chemical tools. Therefore, the development of specific and active autophagy modulators becomes most desirable. Here, we briefly review the regulation of autophagy and then summarize the recent development of small molecules targeting the core autophagic machinery. Finally, we put forward our viewpoints on the current problems, with the aim to provide reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective autophagy modulators.