Extracts of Crataegus spp. have been the subject of extensive in vivo and in vitro investigations, primarily for the treatment of cardiovascular diseases. Effects include antioxidant, hypolipidemic, hypotensive, positive inotropic activity, increased blood vessel wall integrity, improved coronary blood flow, and positive oxygen utilization, among others. Flavonoids and procyanidins are the principle constituents. This chapter reviews published English language scientific literature for evidence of indications of interactive combination effects including synergistic effects and/or multiple target effects within the body. Synergistic effects have only been reported using effect‐based measurement approaches. There was considerable diversity among the studies regarding their methodology, substrate type and their analysis, which made direct comparisons challenging. The authors suggest the need for universal use of consistent and standardized methods, using activity‐led, systems‐based reverse analysis or “omic” research, owing to the multifactorial requirements of plant‐based studies.