IntroductionDespite advances in clinical intervention and drug treatment, cardiovascular disease (CVD) remains a leading cause of mortality worldwide except Africa . According to the Global Burden of Disease Study 2016, the CVD resulted in 17.6 million deaths in 2016, which increased by 14.5% between 2006 and 2016 . As the prevalence of chronic diseases increases steeply with age, it is crunch time for us to understand the biology of CVD and make effort to find new strategies for clinical intervention.However, the pathological process of cardiovascular disease is very complicated, including the control of oxidative stress, inflammation, angiogenesis, cell proliferation, atherosclerosis, tissue repairing and cardiac electrophysiology. In addition to the differential expression of genes, the regulation network of these pathological changes also involves the multiple molecules such as miRNA, lncRNA, and exosomes. Different molecules form a thorough interaction network to jointly regulate the development of CVD.Importantly, mounting evidence suggested significant roles of bioactive small molecules (BSMs) in cardiovascular system. BSMs, which include gaseous signal molecules, small molecules proteins, active peptides, active amino acids and derivatives, amines, lipids, metal ions, etc., play pivotal roles as signaling messengers maintaining cardiovascular homeostasis and in the pathogenesis of many cardiovascular disorders [3, 4]. Therefore, elucidating the dynamic changes and mutual regulatory networks of BSMs and studying their physiological functions of the heart will help reveal important molecular events and explore potential drug targets in the development of cardiovascular disease. It is no exaggeration to say that BSMs provide new insights for the prevention and treatment of cardiovascular diseases.This review summarizes five main features of BSMs in cardiovascular research after a short introduction about the current understanding of BSMs and then analyses current advances and challenges of BSMs in drug discovery and other application in cardiovascular diseases.