We use human skin tissue models that provide a tractable and clinically relevant platform to study epithelial homeostasis as well as tumor progression. Regenerated human skin tissue comprised of primary human keratinocytes within a 3-dimensional intact architecture that includes the basement membrane and human dermal stroma faithfully recapitulates the global gene expression and architecture of actual human skin. Co-expression of oncogenic Ras with Cdk4 to promote G1 escape in this model rapidly converts normal epidermal tissue into invasive neoplasia that reprises cardinal features of human skin cancer and can be placed as a human tissue xenograft on immune-deficient mice for longer studies. Genetic constructs encoding elements of unknown function can be superimposed into these models to assess their effect on homeostasis and tumor progression by highly quantitative metrics. Multiple (>15) alleles can be altered simultaneously within intact tissue, enabling genetic studies to be performed with a degree of complexity that is often challenging with traditional animal models. Genome editing through a combination of CRISPR/Cas9 and recombinogenic adeno-associated virus (AAV) vectors further allows us to introduce cancer-associated mutations in the endogenous alleles of primary cells. These organotypic human skin models enable human disease to be studied in human tissue, which is known to differ significantly in architecture, metabolism, signal transduction, and DNA repair from mouse and is also differentially resistant to carcinogenesis. These models also incorporate key elements of epithelial tumor progression lacking in subcutaneous injection models, including pre-malignant hyperplasia, in situ neoplasia, and invasion of neoplastic cells across the basement membrane into the surrounding stroma.