The proliferative cancer cell paradigm that has driven cancer drug development for the past 50 years has failed to generate treatments that cure most metastatic adult cancers. This view is supported not only by cumulative experience with conventional cytotoxic anticancer drugs, but also by the application of highly-targeted anticancer compounds against, for example, BCR-ABL in CML and mutant BRAF in metastatic melanoma. Such drugs often send their respective cancers into complete molecular remission but fail to effect cures because a small population of quiescent or slowly selfrenewing cancer cells that are drug and radiation resistant survive treatment indefinitely. This review explores the grounds for an emerging cancer paradigm that views cancer as a disorganized tissue with hierarchical cellular compartments in which the boudaries are less well-defined than in normal tissues with plasticity controlled by epigenetic changes mediated by the local microenvironment. Increased metabolic flexibility and adaptability give cancer cells an additional survival advantage that may be able to be targeted with drugs like metformin. Combining approaches that target the increased metabolic flexibility of cancer cells as well as ablating rapidly-proliferating cells and self-renewing cancer stem cells in individual cancers are needed to address the holy grail of cancer cure.