Congestive heart failure (CHF) is a widespread disease that has a negative impact on health, worldwide. Despite advances in therapies, morbidity, mortality and hospital discharges due to CHF remain high. Advances in the understanding of the pathophysiological mechanisms of CHF and the development of gene transfer technology have made gene therapy a realistic potential therapeutic method for CHF. Among the various potential targets, sarco-endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), which is an important protein in the regulation of Ca²⁺ cycling, has piqued the interest of many researchers. Restoring decreased SERCA2a activity in CHF could improve cardiac contractions and energetics, as well as reduce myocardial fibrosis and ventricular arrhythmias, and these benefits have been confirmed by studies using both in vivo and in vitro models. Following these promising preclinical results, SERCA2a gene therapy advanced to clinical trials. However, results of the clinical trials were controversial, leading some to question whether SERCA2a is the right target for CHF treatment. In this review, we illustrate the function and significance of SERCA2a in CHF, and more importantly, analyze possible causes of the controversial clinical trials results, with the aim of stimulating future research on the relationship between SERCA2a and CHF.