Our objective was to screen molecules that could interact with keratin in the human nail and thereby improve the topical penetration of actives into and through the nail plate. We used specialized Franz-type diffusion cells for our permeation experiments and water as a marker molecule. Aqueous/hydroalcoholic gels containing the enhancers were spiked with tritiated water and compared with a control (without enhancer). We computed the normalized water ยฏux (deยฎned as a product of ยฏux and nail thickness) for each gel. We deยฎned an enhancement factor for water as the ratio of the normalized water ยฏux from a gel containing enhancer to that of the control. Our results indicate that the chemical structure of the modiยฎer is most important in determining its ability to enhance penetration. The best enhancement effect was obtained using N-(2-mercaptopropionyl) glycine, a mercaptan derivative of an amino acid, in combination with urea. The concentration of each chemical modiยฎer was linearly related to normalized water ยฏux and mercaptan levels were more important that urea levels in penetration enhancement. Barrier integrity of nails was compromised after treatment with effective chemical modiยฎers. Thus, we have developed a suitable technique to screen nail penetration enhancers using water as a probe.