<p>Despite advances in heart failure management, current therapies largely focus on symptom relief and slowing disease progression, without reversing or preventing the underlying condition. As cardiovascular diseases remain a leading cause of mortality, developing curative treatments is an urgent goal. Advances in understanding the molecular mechanisms of heart failure, alongside insights into pathways that drive cardiac regeneration have opened new avenues for gene therapies aimed at restoring cardiac function. While several gene therapy candidates have advanced to clinical trials, their outcomes have been inconsistent, underscoring the challenge to translating preclinical success into clinical efficacy. In this review, we examine the current landscape of gene therapy strategies for ischemic heart failure, emphasize the importance of robust preclinical models in bridging the gap from bench to bedside, and highlight emerging regenerative approaches that aim to repair damaged myocardium and restore cardiac function.</p>