A multitude of in vivo variables can influence systemic drug absorption after intake of an oral formulation. For the measurement of consistent in vivo parameters within and between pharmacokinetic studies it is of primary importance that such variables be recognized. Consequently, as many variables as possible should be eliminated or controlled by proper study designs to prevent (or minimize) their disturbance of in vitro/in vivo correlations. The possible influences of some important variables are elaborated and discussed in this paper. The influences of food can be anticipated and controlled against the background of gastrointestinal physiology with and without food and its interplay with the dosage form. Food, and also posture and exercise, may influence splanchnic-hepatic blood flow which may substantially affect the absorption of drugs with a high first-pass metabolism. The influence of the discussed variables may be modified by the dosage form of a particular drug. Single dose studies are appropriate for studying immediate release formulations and in the development of controlled release formulations. Multiple dose studies are preferred for the formal validation of controlled release formulations.