The introduction and expression of exogenous genetic material in cultured cells has provided a powerful tool for studying gene function and regulation. Immortalized cell lines have been useful for establishing gene transfer methodologies that are generally inefficient. For investigators of epidermal and mucosal biology, wishing to make use of the tissue architecture produced by primary keratinocytes in vitro, the limited life span of these cells presents a host of unique problems. Primary cells require the use of gene transfer methods that are highly efficient and will not significantly alter the cell's normal differentiation pathway. The purpose of this review is to evaluate gene transfer technology as it applies to keratinocytes.