Heart failure (HF) is a major global health problem afflicting millions worldwide. Despite the significant advances in therapies and prevention, HF still carries very high morbidity and mortality, requiring enormous healthcare-related expenditure, and the search for new weapons goes on. Following initial treatment strategies targeting inotropism and congestion, attention has focused on offsetting the neurohormonal overactivation and three main therapies, including angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists, β-adrenoceptor antagonists, and mineralocorticoid receptor antagonists, have been the foundation of standard treatment for patients with HF. Recently, a paradigm shift, including angiotensin receptor-neprilysin inhibitor, sodium glucose co-transporter 2 inhibitor, and ivabradine, has been added. Moreover, soluble guanylate cyclase stimulator, elamipretide, and omecamtiv mecarbil have come out as a next-generation therapeutic agent for patients with HF. Although these pharmacologic therapies have been significantly successful in relieving symptoms, there is still no complete cure for HF. We may be currently entering a new era of treatment for HF with animal experiments and human clinical trials assessing the value of antibody-based immunotherapy and gene therapy as a novel therapeutic strategy. Such tempting therapies still have some challenges to be addressed but may become a weighty option for treatment of HF. This review article will compile the paradigm shifts in HF treatment over the past dozen years or so and illustrate current landscape of antibody-based immunotherapy and gene therapy as a new therapeutic algorithm for patients with HF.