Cardiovascular disease remains the number one cause of mortality in the United States. Nearly 2,400 Americans die of cardiovascular disease each day, an average of 1 every 37 s. One in three Americans has been diagnosed with one or more forms of cardiovascular disease. Most recent estimates show that, in the United States alone, 16 million people have coronary artery disease and 5.3 million have been diagnosed with heart failure. Unlike other forms of cardiovascular disease, heart failure is often the end-stage of a cardiovascular disease, frequently coronary artery disease. The 1-year mortality of people diagnosed with heart failure remains a sobering 20%. Heart failure is also very costly. The estimated direct and indirect cost of heart failure in the US for 2008 is 34.8 billion dollars. Therefore, advanced treatment options for these populations could greatly impact patient health outcomes and cost savings. Even with the advancements in pharmacologic therapies and improvements in mechanical support devices, the only definitive treatment for advanced heart failure remains heart transplantation. Given the limited availability of donor organs for use in orthotopic heart transplantation, alternative therapies including stem cell-based therapies have been explored. The past decade has seen an explosion of activity of the field of cardiac regeneration. New scientific techniques and discoveries have allowed rapid advancements but there have also been conflicting opinions and results. The concept of cardiac regeneration is now commonly accepted but the exact mechanisms and extent of regeneration is greatly debated. Several candidate cell populations, both cardiac and extracardiac, have been reported to be capable of cardiac regeneration. However, some studies question if these cell populations actually differentiate into cardiomyocytes but rather function through paracrine effects or through cell fusion. Despite these challenges, the field has also begun translating the preclinical animal studies into human clinical trials using several cell types for the treatment of many clinical disease states. This review will highlight the preclinical animal studies and review the results of the published clinical trials.