Chemical penetration enhancers are widely used in transdermal pharmaceuticals as well as cosmetic products. Selection of suitable enhancers in topical formulations requires an understanding of the mechanism of action of these enhancers. The objective of the present study was to evaluate the enhancement effects of a number of commonly known enhancers and cosmetic ingredients on permeation across human epidermal membrane (HEM). The potencies of these chemical enhancers-maximum enhancement, E max -were compared at their highest thermodynamic activity in equilibrium with HEM (i.e., solubility equilibrium). This was achieved by the treatment of HEM with the enhancer or phosphate buffered saline (PBS) saturated with the enhancer. Passive transport experiments were then conducted with a model permeant corticosterone to determine the effects of these enhancers on the lipoidal pathway of HEM. The results suggest that E max of an enhancer is related to its octanol/water partition coefficient and its solubility in the HEM lipid domain. A relationship between enhancer E max and its solubility in silicone elastomer was also observed, suggesting the use of silicone solubility to predict enhancer potency. Based on the E max results, some common topical ingredients were found to be more potent enhancers than a number of well-known chemical enhancers.