The recent discovery of human-induced pluripotent stem cells (iPSC) has revolutionized the field of stem cells. iPSC have demonstrated that biological development is not an irreversible process and that mature adult somatic cells can be induced to become pluripotent. This breakthrough is projected to advance our current understanding of many disease processes and revolutionize the approach to effective therapeutics. Despite the great promise of iPSC, many translational challenges still remain. The authors review the basic concept of induction of pluripotency as a novel approach to understand cardiac regeneration, cardiovascular disease modeling, and drug discovery. They critically reflect on the current results of pre-clinical and clinical studies using iPSC for these applications with appropriate emphasis on the challenges facing clinical translation.