Our lab studies the skin, which serves as a protective shield between the human body and its environment. This critical barrier tissue is tasked with sealing the body to prevent water loss, excluding pathogens like bacteria to avoid infection, and withstanding damage from environmental insults like ultraviolet radiation to resist cancer formation. The epidermis is made up of multiple layers of cells called keratinocytes, which must continually replicate themselves to replenish the skin tissue as it is naturally shed every month. While keratinocytes slowly move outward toward the skin surface, they must undergo a unique process of maturation to harden and strongly adhere to one another to protect the body and resist wounding. Unfortunately, keratinocyte maturation is disrupted in many human skin diseases like eczema and psoriasis or in rare genetic disorders like ichthyoses. These diseases can cause widespread flaky, itchy, painful, and wounded skin. Our understanding of the biology of keratinocyte maturation is limited and this has prevented development of effective therapies to promote regeneration of the epidermis after wounding and limits our ability to treat inherited skin disorders. To address this knowledge gap, I have optimized a laboratory “organoid” model of the epidermis in which human keratinocytes form a multi-layered tissue in just 1 week. We can engineer the keratinocytes to express fluorescent proteins that are visible using a high-magnification (confocal) microscope. This technique permits us to visualize changes in the live tissue model at the level of single organelles (e.g., mitochondria) to better understand how the epidermis forms. As well, we can use genetic engineering to alter the DNA of human keratinocytes to make them harbor mutations found in human skin disorders in order to model those diseases in the lab. These skin tissue models can then be treated with chemicals that might serve as new medications. Ultimately, we aim to use our lab’s findings to identify novel treatment strategies to promote epidermal tissue regeneration after skin injuries and to restore skin barrier function in inherited and currently incurable dermatologic diseases lacking effective therapies.