Over the past 20 y, evidence derived from in vitro experiments, animal models, observational studies, and clinical interventions have suggested that cacao (cocoa) flavonoids act through a variety of mechanisms to modify a number of risk factors associated with chronic conditions, including cardiovascular and neurodegenerative diseases. Recent studies have elucidated the synthesis of flavonoids by plants, making available for research specific flavonoids and their metabolites. The body of evidence suggesting that cocoa flavanols may play a role in reducing the risk of cardiovascular disease has been sufficient to generate several systematic reviews and meta-analyses. Studies are now being directed to identify the molecular pathways underlying the effect of cocoa flavanols, and clinical trials are being planned to test their impact on disease endpoints.