The parallel artificial membrane permeability assay (PAMPA), as a passive-permeability screen, is a possible low-cost alternative to cellular models for the earliest ADME primary screening of research compounds. Its popularity in the industry has risen rapidly. This review examines state-of-the-art PAMPA methods. The various covered topics include: different lipid formulations, the quantitative relationships between hexadecane, dioyleyoylphosphatidycholine and Double-Sink PAMPA measurements, the use of individual-well stirring, issues of ultraviolet sensitivity, timing strategies, reproducibility of measurements, the correct pH to perform the measurement to avoid aqueous boundary layer problems, the pKa(flux) method for determining intrinsic permeability coefficients and the cosolvent method for very insoluble molecules. Examples of the determination of permeability of very difficult molecules, but molecules that are well absorbed, are given. Carefully gathered evidence in support of the use of the Double-Sink PAMPA model is presented. The review concludes with a binning strategy to predict human intestinal absorption, based on the use of the sum of permeability coefficients, measured at gradient pH 5.0, 6.2 and 7.4. Opinions regarding the future of PAMPA are offered.