Use of gene therapy for heart failure is gaining momentum as a result of the 
recent successful completion of phase II of the Calcium Upregulation by 
Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, 
which showed clinical safety and efficacy of an adeno-associated viral vector 
expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a). Resorting to 
gene therapy allows the manipulation of molecular targets not presently amenable 
to pharmacologic modulation. This short review focuses on the molecular targets 
of heart failure gene therapy that have demonstrated translational potential. At 
present, most of these targets are related to calcium handling in the 
cardiomyocyte. They include SERCA2a, phospholamban, S100A1, ryanodine receptor, 
and the inhibitor of the protein phosphatase 1. Other targets related to cAMP 
signaling are reviewed, such as adenylyl cyclase. MicroRNAs are emerging as 
novel therapeutic targets and convenient vectors for gene therapy, particularly 
in heart disease. We propose a discussion of recent advances and controversies 
in key molecular targets of heart failure gene therapy.