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Metastatic cancer is ultimately resistant to virtually all systemic therapies and continues to kill more than 10 million people per year around the world. This suggests a common mechanism for cancer resistance that evolves in millions of people each year, regardless of the instigating carcinogens, suite of mutations present in the tumor, or the tissue of origin. This therapeutic resistance has classically been attributed to genetic tumor cell heterogeneity that develops by stochastic chance, fueled by aneuploidy and genetic instability. In this classic view, resistance to each different therapy requires that the appropriate mutations that confer the different versions of resistance are acquired by at least one cell. Newer models have found potential evidence for the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes of multiple partially resistant clones as well as the presence of cancer stem cells in which a rare therapy-resistant population of cancer stem cells give rise to a recurrent, resistant population.