Cardiovascular diseases are a group of multifactorial and complex debilitating diseases facing limitations in classical pharmacology. Instead of drug-targeting the consequences, the origin of the disease (i.e. cardiomyocytes degeneration) represents a better although challenging target. Indeed, the human heart is not or poorly able to regenerate. The loss of cardiomyocytes, occurring in many ischemic or genetic cardiac diseases, replaced by fibroblasts leads to a lower response of the myocardium to the contractile demand. Following a transient compensatory hypertrophic phase, and despite the intervention of pharmacological agents to limit the contractile demand, including beta-adrenoceptors blockers or inhibitors of the conversion enzyme, the contractile force developed reaches a limitation dropping the myocardium into a failing stage. Thus, myocardial regeneration has been envisioned using 'pharmacological' agents, genes, or stem cells. For the past decade, both gene therapy and more recently cell therapy have been tested in clinical trials to relieve some aspects of heart weakness or to compensate myocardial degeneration. Protein-based and miRNA-based regenerative therapies are also emerging from experimental animal studies. This review brings an update on the most recent research strategies to regenerate the diseased myocardium. The remaining challenges of gene-based, cell-based, or protein-based therapies to relieve heart failure are discussed.