The potential toxicity of a new drug, chemical or cosmetic, has to be ascertained before the substance can be placed on the market. Since the number of new drugs that appear on the market each year is prodigious, toxicity testing is a major enterprise for pharmaceutical, household, cosmetic, and chemical companies in the developed world. To aid in this testing several new in vitro models have been produced recently including a three-dimensional skin construct, Skin(2(TM)). This product consists entirely of human skin cells. The advantages of using human skin cells vis-a-vis rodent cells are reviewed, as is the concept that the operational mechanisms in the human skin immune system may be significantly different from those in murine skin. Finally, recent data using Skin(2(TM)) to assay cytokine production after various treatments or injuries are reviewed, especially as regards to irritancy reactions.