Heart failure continues to be the leading cause of morbidity and mortality not only in the United States but throughout the world. Despite advances in medical and device therapy, many patients continue to have significant symptoms leaving heart transplantation, left ventricular assist devices (LVAD), or palliative care as the only options. This has stimulated interest in regenerative therapies including stem cell therapy. Based on positive preclinical results, the initial clinical trials used predominantly autologous bone marrow mononuclear stem cells (BMC). Trials with BMC demonstrated excellent safety but only modest efficacy most likely due to the significant variability with autologous BMC which is related to the decline in the number and potency of stem cells with age and cardiac risk factors. This has stimulated the next generation of cell therapies which include allogeneic cells, cardiac derived cells, and enhanced cultured autologous cells. A recent large double-blind, placebo controlled Phase 2 trial using enhanced BMC cells (IxCell-DCM) demonstrated a significant reduction in mortality and cardiovascular hospitalizations in cell-treated patients. A second large Phase 2 trial using enhanced mesenchymal stem cells (MSCs) will be presented at ESC and a large Phase 3 trial with allogeneic MSCs is underway. An even more attractive idea is to combine the benefits of novel, mechanical left ventricular support devices with regenerative therapy. To date, there have been a total of 67 patients randomized in 11 published clinical trials with the combination of cell therapy and LVAD trials. The largest of these (N=30) was an NIH-sponsored trial using allogeneic MSCs which demonstrated a potential benefit in LVAD weaning and a suggestion of mortality benefit. In summary, despite optimal medical and device therapy the number of patients with advanced HF continues to grow. Both novel mechanical assist devices and regenerative therapy represent potential solutions. The combination of these two unique therapies may be a particularly attractive solution.