Invasion of the surrounding tissue by malignant epithelial cells is a complex process. It involves degradation of basement membrane and stromal connective tissue elements and movement of tumor cells into and through the partially-degraded matrix. While the process of tumor cell invasion has been extensively studied in simple two-dimensional or three-dimensional assay systems, it is difficult to know how the cellular and molecular mechanisms that underlie invasion in these culture systems relate to mechanistic events that drive invasion in intact tissue. To help address this question, our laboratory has developed a human skin organ culture model to study epithelial cell invasion of the stroma in intact tissue. In this model, punch biopsies of human skin are maintained in organ culture under serum-free, growth factor-free conditions or in the same culture medium supplemented with exogenous epidermal growth factor (EGF). In the absence of growth factor stimulation, normal tissue architecture and biochemical function are preserved. However, in the presence of exogenous EGF, the dermal-epidermal juncture is eroded and epithelial cells invade the dermis. Concomitant with dermal invasion is induction of matrix metalloproteinases (MMPs), stimulation of fibronectin synthesis and active epithelial cell migration into the stroma. These observations provide convincing evidence that events thought to be involved in invasion in simple two- and three-dimensional in vitro models are also operative during invasion of intact tissue.