Flavonoids are a large group of plant polyphenols with presumed beneficial effects on several common diseases. The use of dietary supplements enriched with flavonoids is becoming increasingly popular. These polyphenols are substrates of enzymes like cytochrome P450 monooxygenases and phase II conjugation enzymes, as well as of drug transporters involved in drug excretion. Thus, they share the same metabolic pathways with many therapeutic drugs. A number of studies have demonstrated inhibition of various cytochrome P450 monooxygenases and drug transporters by flavonoids. Flavonoid-induced effects on drug bioavailability were also shown. This raises concerns about the safe use of flavonoid supplements and flavonoid-containing remedies which are not subject to legal regulations. The challenge is to find a suitable way to predict harmful drug-flavonoid interactions.