Many important advances have been made in the phenotypic and genetic characterization of malignant tumors since the publication of Peter Nowell’s seminal article on the origin of cancer, but there has been no consistent effort to incorporate this wealth of knowledge into a general model of carcinogenesis. Current theoretical discussions on cancer are frequently dominated by attempts to categorize genetic alterations and phenotypic characteristics and establish correspondences between them. In this article, I argue, on the basis of recent data as well as “old” observations, that a developmental error leading to the acquisition of a unique cell character (de-differentiation) underlies all phenotypic characteristics of cancer cells and discuss how this notion can be reconciled with Nowell’s model of carcinogenesis as a microevolutionary process into an updated theoretical description of cancer.