There is emerging evidence from clinical studies that the existence of liver cancer stem cells(CSCs)or tumor initiating cells is responsible for the high recurrence rates of tumor,generation of metastasis,and resistance to therapeutic regimens after therapy. Here,the characteristics of liver CSCs,clinical manifestation,molecular signaling Wnt/β-catenin,signal transducers and activators of transcription 3,NANOG,annexin A3/c-Jun N-terminal kinase,and chapter four-transmembrane 4 L six family member 5/CD44 in liver CSC self-renewal were briefly reviewed. In addition,potential targets for drug therapy were analyzed,providing some reference for drug discovery that selectively target liver CSC self-renewal signals.