Several biological principles such as epigenetic changes, RNA interference, epithelial-mesenchymal transition, and cancer stem cell formation have been recently connected to the pathobiology of tumors. All these phenomena have, along with genetic changes, a significant impact on the neoplastic transformation and/or tumor progression. Authors report a review of the above mentioned "nongenetic" processes and their effect on the neoplastic transformation, and the appearance, behavior, prognosis, and therapy of tumors. Future diagnostic and therapeutic perspectives are also discussed.