The use of mesenchymal stem cells (MSC) for tissue repair has garnered much interest and has been evaluated in several disease settings. Recent evidence indicates that the beneficial effects observed with MSC-based therapy can be mediated through the paracrine release of extracellular vesicles and other soluble proteins or biologically active molecules, which collectively constitute the MSC secretome. In this concise overview, we highlight results from preclinical and other studies that demonstrate the therapeutic efficacy of the MSC secretome for diseases that are characterized by liver injury or fibrosis. The potential for the use of the MSC secretome as an acellular regenerative therapy and approaches for the isolation of a secretome product for therapeutic applications are highlighted. The use of the MSC secretome as an acellular therapeutic agent could provide several advantages over the use of cell-based therapies for liver diseases.