Since the first human hepatocyte transplants in 1992, clinical studies have clearly established proof of principle for this therapy as a treatment for patients with acquired or inherited liver disease. Our laboratory has always been active in the translation of hepatocyte transplant technology from bench to clinic. Twenty years of experience in isolating hepatocytes leaded us to specifically designed and optimized GMP procedure to isolate human cells for clinical applications. Although major accomplishments have been made, there are still some specific limitations to this technology to a wider range of clinical applications, which, if overcome, could greatly enhance the efficacy and implementation of this therapy. Here, we describe what in our view are the most significant obstacles and review the solutions recently proposed. The obstacles of significance include the limited number and quality of liver tissues as a cell source, the lack of clinical grade reagents, quality control evaluation of hepatocytes and hypothermic storage of cells prior to transplantation, pre-conditioning treatments to enhance engraftment and proliferation of donor cells, tracking or monitoring cells after transplantation, and the optimal immunosuppression protocols for transplant recipients. In addition we briefly described a new stem cell-based clinical approach highly promising in treatment of several liver diseases.