Allergic contact dermatitis (ACD) is a cell-mediated immune response to small molecular weight chemicals that contact and penetrate the skin. There are a variety of characteristics that determine whether a chemical can function as a contact sensitizer (or allergen) including the ability to penetrate into the skin, react with protein and be recognized as antigenic by immune cells. The ultimate challenge for developing non-animal test methods for skin sensitization testing will be applying our mechanistic understanding of ACD to the design of predictive in vitro alternative test methods. Specifically, the in vitro approach should be designed so that a chemical's potential to penetrate the skin, react with protein/peptide (biotransformation may be required) and initiate an antigen-specific immune response is incorporated in the test methods developed. In this review, we have focused on cellular-based assays that have been developed or proposed for assessing a chemical's skin sensitization potential in vitro. All of the promising leads to date are based on observations made from in vivo studies conducted in animals and humans, and therefore have a strong mechanistic foundation. However, it remains to be demonstrated whether a single in vitro test, or several in vitro tests in combination, which model the critical steps in sensitization, can replace animal experiments for predicting contact allergic reactions in humans. Regardless, the future looks promising with continued development of our understanding of the chemical and biological aspects of allergic contact dermatitis, and most importantly, with the application of genomics/proteomics to this field on the immediate horizon.