Clinical studies suggest that stem cell transplantation (SCT) is feasible and has the potential for beneficial effects in several cardiac affections, including myocardial infarction and advanced heart failure. However, concern exists about the possible occurrence of serious arrhythmias after SCT, even if such complication has been shown only in case of skeletal myoblast transplantation. SCT might induce arrhythmias by several mechanisms, such as electrotonic stimulation of cardiac cells, electrical heterogeneity of action potentials during stem cell differentiation process, increased nerve sprouting, and local tissue injury induced by intramyocardial injection. As a matter of fact, the use of endothelial progenitor cells from the peripheral blood or of stem cells from bone marrow has not been associated with any significant cardiac rhythm disturbance. Recently, a new opportunity for SCT has emerged: the development of a biological cardiac pacemaker. Both gene therapy and cell therapy have been used in this new perspective. In fact, at present, the transformation of a normal cardiomyocyte in a pacemaker cell can be obtained in animal models by the injection of a plasmid or virus, incorporating the gene encoding for specific proteins. This procedure transforms cardiomyocytes in transgenic cells that may show an overexpression of beta2-adrenergic receptors, or abnormal membrane ion channels. As an alternative, genetically modified mesenchymal stem cells can be delivered within the heart and engraft to develop a biological pacemaker. To date, several studies have been performed in different animal models employing both cell and gene therapy. However, complex problems concerning safety and efficacy require a solution before we can move to the step of clinical evaluation in human beings.