Many products and chemicals cause irritation when they contact the skin. Whole animal primary irritation testing (Draize test) has been around since 1944 with many modifications and variations. Because chemicals diffuse through the skin at different rates and have different irritant potencies, there is an exposure duration for most substances that would not cause irritation. Only minutes of contact could be safe for some substances but it might take hours or days for other substances to cause irritation. The general purpose of these studies is to characterize the biological cascade in the skin that results from acute chemical exposure. Ultimately our goal is to develop a biologically based model of irritation that can be used to predict safe exposure durations for a wide variety of compounds. We exposed rats, in vivo, to irritating chemicals for one hour and investigated the temporal changes in gene expression and protein levels. Traditional histopathology and immunohistochemistry were also used to compare response of the skin to the fuel and solvents. We found that the parameters in the irritant cascade that we investigated responded differently depending on the degree of irritancy of each chemical. Measurements of protein levels will refine our preliminary understanding of this acute irritant cascade.