The last decade has seen the complete sequencing of the human genome and the development of approaches to deliver therapeutic genes to the heart. Equally significant advances have also been made in stem cell biology. The accessibility of these new tools in our therapeutic arsenal raises the exciting question of whether normal mechanical and electrical function can now be regenerated in the diseased heart. In this article, we consider how to choose targets to regenerate mechanical and electrical function. In considering mechanical function, we start by describing its determinants (ie, both active and passive properties), and then review regenerative applications of gene/cell therapy. We also consider arrhythmias, focusing on the potential advantages of gene/cell therapy over pharmacotherapy or devices, and then discuss the development of biological pacemakers as one example. Overall, the future is bright; gene/cell therapy approaches have reached the proof-of-principle stage for both mechanical and electrical regeneration. Some mechanical studies have even reached clinical trials; however, evidence of long-term efficacy is lacking. Ultimately, to achieve therapeutic success with gene and cell therapies, it will be important to gain a better understanding of their mechanisms of action...