Abstract: 　　
　　Human caseinolytic peptidase P (hClpP) is a serine protease located in the matrix of mitochondria. The primary function of hClpP is to maintain the functions of mitochondria by degrading damaged or misfolded mitochondrial proteins. Many cancer cells have high expression level of hClpP, and their survival and proliferation have high reliance on hClpP, therefore, hClpP has been recognized as a promising target for the development of novel anticancer drugs. Small molecular activators of hClpP can activate hClpP, induce the degradation of its substrates in mitochondria, and thus promote the death of cancer cells with high reliance on hClpP. In this review, we first introduced the structure and function of hClpP, then summarized the recent progress in the development of small molecular hClpP activators, and last provided prospect for their potential application in the treatment of human cancers.