The effect of various vehicles (polyacrylate gels and wool alcohol ointments) on the penetration of flufenamic acid into excised human skin was investigated. Physico-chemical properties of the formulations were examined and discussed. Penetration data was gathered using two different in vitro test systems: the Saarbruecken penetration model (SB-M) and the Franz diffusion cell (FD-C). With wool alcohol ointments, drug concentration in the formulation was the decisive parameter for drug liberation and penetration. The incorporation of water into wool alcohol ointment led to increased drug amounts within the deeper skin layers (DSL), especially after longer incubation times. The drug concentration within the stratum corneum (SC) was not influenced by the bleeding effect of lipophilic, liquid components of the various wool alcohol ointments. With polyacrylate gels different results for liberation and penetration were observed. These results could be related to the effects of the drug concentration within the formulation and the penetration enhancers incorporated into the gels. Especially the effects of penetration enhancers clearly illustrated that liberation experiments do not predict the situation in the skin, but make experiments with a biological barrier essential. The high water content of the gels led to hydration of the skin specimen for the SB-M and the FD-C and therefore, in contrast to previous findings, comparable data were obtained in the penetration studies with both models. Furthermore, the quasi steady-state drug amount in the SC could be calculated for all formulations using an equation derived from a Michaelis–Menten kinetics. The data from both test systems were linearly correlated to each other. In addition, a direct linear relationship between the SC drug amount and the drug amount in the DSL was found as long as the quasi steady-state drug amount in the SC was not reached. A combination of all results might offer the chance to reduce the costs and to simplify the development of a new drug formulation.