Abstract: Caspase-3 plays a very important role in the apoptotic cascade as the downstream key executioner caspase. Identification of small molecules that restart the apoptosis of tumor cells by directly activating over-expression procaspase-3 to active caspase-3 has become an effective strategy for overcoming the mutation of the middle/upstream apoptotic protein. Currently, some procaspase-3 small molecule activators have been reported, but no marketed drugs are available so far. The development of procaspase-3 activator remains an important and difficult challenge. In this article, the relationship between procaspase-3 and tumor and the research progress of procaspase-3 small molecule activators were introduced.