Mathematical modeling of skin transport is considered a valuable alternative of in-vitro and in-vivo investigations especially considering ethical and economical questions. Mechanistic diffusion models describe skin transport by solving Fick’s 2nd law of diffusion in time and space; however models relying entirely on a consistent experimental data set are missing. For a two-dimensional model membrane consisting of a biphasic stratum corneum (SC) and a homogeneous epidermal/dermal compartment (DSL) methods are presented to determine all relevant input parameters.The data were generated for flufenamic acid (M W 281.24g/mol; logKOct/H2O 4.8; pK a 3.9) and caffeine (M W 194.2g/mol; logKOct/H2O −0.083; pK a 1.39) using female abdominal skin. K lip/don (lipid-donor partition coefficient) was determined in equilibration experiments with human SC lipids. K cor/lip (corneocyte-lipid) and K DSL/lip (DSL-lipid) were derived from easily available experimental data, i.e. K SC/don (SC-donor), K lip/don and K SC/DSL (SC-DSL) considering realistic volume fractions of the lipid and corneocyte phases. Lipid and DSL diffusion coefficients D lip and D DSL were calculated based on steady state flux. The corneocyte diffusion coefficient D cor is not accessible experimentally and needs to be estimated by simulation.Based on these results time-dependent stratum corneum concentration-depth profiles were simulated and compared to experimental profiles in an accompanying study.