Lipid-bilayer permeation is determinant for the disposition of xenobiotics in the body. It controls the pharmacokinetic behavior of drugs and is, in many cases, a prerequisite for intracellular targeting. Permeation of in vivo barriers is in general predicted from lipophilicity and related parameters. This article goes beyond the empirical correlations, and elucidates the processes and their interplay determining bilayer permeation. A flip-flop model for bilayer permeation, which considers the partitioning rate constants beside the translocation rate constants, is compared with the diffusion model based on Fick's first law. According to the flip-flop model, the ratios of aqueous volumes to barrier area can determine whether partitioning or translocation is rate-limiting. The flip-flop model allows permeation of anions and cations, and expands our understanding of pH-dependent permeation kinetics. Some experimental evidences for ion-controlled permeation at pH 7 are also included in this work.