Despite the continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of the human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires molecular machinery necessary to eliminate the cytotoxic effect of the treatment. However, the emergence of a resistant phenotype is not in itself clinically significant. That is, resistant cells affect patient outcomes only when they succeed in the second step of resistance by proliferating into a sufficiently large population to allow tumor progression and treatment failure. Importantly, proliferation of the resistant phenotype is by no means certain and, in fact, depends on complex Darwinian dynamics governed by the costs and benefits of the resistance mechanisms in the context of the local environment and competing populations. Attempts to target the molecular machinery of resistance have had little clinical success largely because of the diversity within the human genome-therapeutic interruption of one mechanism simply results in its replacement by an alternative. Here we explore evolutionarily informed strategies (adaptive, double-bind, and extinction therapies) for overcoming treatment resistance that seek to understand and exploit the critical evolutionary dynamics that govern proliferation of the resistant phenotypes. In general, this approach has demonstrated that, while emergence of resistance mechanisms in cancer cells to every current therapy is inevitable, proliferation of the resistant phenotypes is not and can be delayed and even prevented with sufficient understanding of the underlying eco-evolutionary dynamics.