A technique for genetic modification of hair follicles was developed which results in efficient alteration of the hair shaft phenotype. High-level in vivo transgene expression was maintained in hair follicles such that growing hair shafts were phenotypically altered. Mouse anagen skin fragments, maintained in histoculture, were genetically modified at high efficiency with adenoviral-GFP. The histocultured skin fragments were treated with collagenase which made hair follicles accessible to the adenoviral GFP gene, allowing high-efficiency transduction. These skin fragments were subsequently grafted on to nude mice where GFP was readily visualized in as many as 75% of hair follicles. Most follicles produced GFP-fluorescent growing hair shafts. This technique has produced efficient genetic modification of the hair shaft.