Cardiovascular disease is a major cause of death worldwide, with high prevalence and morbidity. Recent advances in technology have reported that abnormalities in the gut microbiota are associated with a variety of diseases, including cardiovascular diseases. The gut microbiota is a complex ecosystem that plays an important role in maintaining host health. It has been reported that the imbalance of gut microbiota causes changes in the production of substances derived from gut bacteria, such as short-chain fatty acids, trimethylamine-N-oxide, and lipopolysaccharide, and contributes to the development of cardiovascular diseases. In the drug discovery, it is a promising approach to prevention and therapy of the cardiovascular disease to focus on the relation between gut and heart, such as gut bacteria. However, there are challenges that must be overcome to convert this approach into effective therapy. In this review, we focus on cardiovascular diseases, particularly atherosclerotic disease, heart failure, and atrial fibrillation, and discuss the relationship between gut bacteria and substances derived from gut bacteria in cardiovascular disease. We also discuss the challenges and potential of drug discovery targeting the gut-heart relationship for the treatment and prevention of cardiovascular disease.