Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.