Cardiovascular disease covers the various disorders like ischemic heart disease, hyperlipidemia, atherosclerosis, myocardial infarction, and hypertension etc. There are many synthetic drugs are available for the treatment of cardiovascular therapy, but they have several drawbacks like high dosing, toxicity, elevated blood potassium levels, low blood pressure, and gastrointestinal issues etc. To overcome these side effects of synthetic drugs by targeting the drug to the specific cardiac tissue is the best novel method in the cardiovascular therapy. The highest targeting efficacy of Ligand-based therapy with proper mechanisms and improved expandability provides a novel therapeutic strategy in the cardiovascular disease. Ligand therapy is cost-effective compared to cell-based therapy. The surface area of protein has much larger than the orally bioavailable drug. So, the targeting of various less active drug molecules to the particular ligand can be possible. The efficacy of ligands to induce cardiomyocytes proliferation has been ratified and point out the fact that ligand-based approaches are effective for cardiac transformation. Ligands interact with proteins in target cells, which are influenced through the chemical signals. These various receptors possess selective binding of biased ligands and also energizing the intracellular signaling pathway. The ligands can directly stabilize the active receptor conformations by a non-standard connective site. The key function of ligands is functional selectivity, which enhances the therapeutic efficacy and minimizes the side effects of drugs through the interpretation of signal transduction pathways. This review covers the role and effectiveness of novel ligands in the cardiovascular disorders.