Background- Cardiovascular diseases, including myocardial infarction, dyslipidaemia and coronary artery pathology, are a major cause of illness and death in Western countries. Therefore, identifying effective therapeutic approaches and their cellular signalling pathways is a challenging goal for medicine. In this regard, several epidemiological studies demonstrate a relationship between the intake of flavonoid-rich foods and the reduction of cardiovascular risk factors and mortality. In particular, flavonoids present in citrus fruits, such as oranges, bergamots, lemons and grapefruit (95% from flavanones), are emerging for their considerable nutraceutical value. Methods- In this review an examination of literature was performed while considering both epidemiological, clinical and pre-clinical evidence supporting the beneficial role of the flavanone class. We evaluated studies in which citrus fruit juices or single flavanone administration and cardiovascular risk factors were analysed; to identify these studies, an electronic search was conducted in PUBMED for papers fulfilling these criteria and written in English. Results- In addition to epidemiological evidence and clinical studies demonstrating that fruits in the Citrus genus significantly reduce the incidence of cardiovascular disease risk, pre-clinical investigations highlight cellular and subcellular targets that are responsible for these beneficial effects. There has been special attention on evaluating intracellular pathways involved in direct cardiovascular and cardiometabolic effects mediated by naringenin, hesperetin and eriodictyol or their glycosylated derivatives. Conclusions- Although some mechanisms of action remain unclear and bioavailability problems remain to be solved, the current evidence supports the use of a nutraceutical approach with citrus fruits to prevent and cure several aspects of cardiovascular disease.