Cardiovascular disease remains the main cause of mortality in the 21st century. Hypertension, vessel atherosclerosis, and familial hypercholesterolemia (FH) are responsible for increased mortality and morbidity in patients. Therapies for cardiovascular disease are based on drug treatment options, but in the era of precision medicine, personalized treatments are being developed. Studies have shown that these conditions have a strong genetic background, creating an opportunity for the implementation of gene therapy for these diseases. Currently, gene therapy is not widely used in clinical practice. Recent advances in this research field are making gene therapy a very promising preventive and therapeutic tool for cardiovascular disease. Essential hypertension’s (EH) pathophysiology is mostly based on the activation of both the sympathetic nervous system and the renin angiotensin aldosterone system (RAAS), natriuretic peptide production, and endothelial dysfunction. Plasmid DNA and viral vectors can be used, targeting the main mechanisms in the pathogenesis of EH. Many preclinical studies have been developed across the years, presenting a significant decrease in blood pressure. Nevertheless, no clinical studies have been developed studying the implementation of gene therapy in EH. Atherosclerotic damage is caused by monogenic diseases or is deteriorated by the activation of inflammation in the vessel wall. Gene therapy studies have been developed in the pre- and clinical phases targeting the lipoprotein and cholesterol metabolism and the inflammation of the vessels. FH is a common inherited metabolic disease associated with high levels of cholesterol in the blood. Clinical trials of gene therapy have been developed and presented optimistic results. In this review, the challenges of gene therapy for cardiovascular disease are outlined. Nevertheless, more clinical trials are needed to be performed for the development of convenient and safe drug schemes for our patients.