Grapefruit juice (GFJ) interacts with a number of drugs, and can alter pharmacokinetics parameters of the drugs. As for these interactions, most reports have focused on the elevation of drug bioavailability by GFJ, but a few recent reports have indicated that GFJ reduced the absorption of drugs not metabolized by cytochrome P450 (CYP). The predominant mechanisms of GFJ-drug interaction are thought to be due primarily to the inhibition of intestinal CYP3A4 activity without an apparent inhibition of hepatic CYP3A4. GFJ is also an inhibitor of P-glycoprotein, an efflux pump in intestinal cell wall enterocytes, although clinical support for this mechanism remains unclear. In addition, GFJ has recently been shown to be a potent in vitro inhibitor of the organic anion-transporting polypeptides (OATP) 1A2, intestinal uptake transporters of structurally anionic drugs. It is therefore noteworthy that intestinal OATPs-mediated drug uptake are reduced by GFJ. The furanocoumarins, major active ingredients in relation to GFJ-drug interaction, were detected in fresh grapefruit, commercial GFJ and seville orange juice. However, the specific furanocoumarins responsible for the inhibition of CYP3A4 activity in in vitro study have yet to be fully determined and corresponded with GFJ effects in in vivo study. This article summarizes our data concerning GFJ-drug interaction and many GFJ-drug effects, and reviews the mechanism of this interaction, possible active ingredients and clinical implications.