Current advances in stem cell research and tissue engineering augur well for the development of improved cultured skin equivalents. Considerable progress has been made in the culture of skin epithelial stem cells, making it possible to obtain a large amount of cultured epithelial cell sheets (from a small skin biopsy) to resurface extensive burns and save lives. However, for over four decades, controversial use of animal products in the cell culture system, flagged as a safety concern, has been ongoing without any notable breakthrough. Here, we describe our attempts to break out from this traditional but restrictive cell culture technique to treat conditions beyond acute burns, such as genetic skin diseases and chronic wounds.