OBJECTIVE A novel technique is presented for identifying potential chemical penetration enhancers (CPEs) based on changes in the electrical resistance of skin. METHODS Specifically, a multi-well resistance chamber was designed and constructed to facilitate more rapid determination of the effect of CPEs on skin resistance. The experimental setup was validated using nicotine and decanol on porcine skin in vitro. The multi-well resistance chambers were capable of operating at 37 degrees C in order to simulate the physiological temperature of the human body. Further, the utility of the multi-well resistance chamber technique was validated using standard Franz diffusion cells. Electrical resistance measurements were used to evaluate the potency of seven new potential CPEs, identified using virtual screening algorithms. From the resistance measurements, the chemicals 1-dodecyl-2-pyrrolidinone (P), menthone (M) and R(+)-3-amino-1-hydroxy-2-pyrrolidinone (C) were identified as the better penetration enhancers among the seven tested. Further, traditional permeation experiments were performed in Franz diffusion cells to confirm our findings. RESULTS The permeation test results indicated that, of the three CPEs deemed potentially viable using the newly-developed resistance screening technique, both P and M increased the permeation of the test drug (melatonin) through skin in 48 h. CONCLUSIONS In summary, this resistance technique can be used to effectively pre-evaluate potential CPEs, thereby reducing the time required to conduct the permeability studies.