This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the available data suggest that the absolute bioavailability of CBD after oral dosing under fasting conditions is approximately 6%, and increases fourfold when the medication is co-administered with a high-fat meal. Based on measurements of CBD plasma exposure after oral dosing and a 6% absolute oral bioavailability estimate, the actual clearance of CBD in adults can be inferred to be in the order of 67 L/h, which is similar to the value of 74 ± 14 L/h (mean ± standard deviation) determined after intravenous injection of a 20-mg dose of deuterium-labeled CBD in five healthy subjects. Assuming that the CBD blood-to-plasma ratio is about 1, as in the case of tetrahydrocannabinol (THC), and that CBD metabolism takes place virtually entirely in the liver, it can be estimated that about 70 to 75% of an orally absorbed dose of CBD can be removed by hepatic metabolism before reaching the systemic circulation, and additionally CBD gastrointestinal absorption is incomplete. A formulation with improved biopharmaceutical properties could increase the extent of CBD absorption about fourfold (i.e., to the level achieved with the currently available formulations co-administered with a high-fat meal) and minimize the influence of food effects on CBD bioavailability. There is also potential for favoring the absorption of CBD through the enteric lymphatic system, thereby reducing the extent of presystemic hepatic elimination. Evidence that CBD can behave as a high hepatic clearance compound also has implications when predicting the magnitude of drug-drug interactions affecting CBD metabolism. These considerations have important clinical relevance, particularly with respect to the objective of minimizing pharmacokinetic variability and consequent intra- and interindividual differences in therapeutic response and susceptibility to adverse effects.