<p>The recurrence of clinically advanced cancers is an evolutionary consequence of standard-of-care chemotherapies generally administered at maximum tolerated doses to kill as many cancer cells as possible. The inevitable appearance of resistance raises the possibility of shifting treatment goals from complete tumor eradication to long-term disease control. The latter approach is employed by adaptive therapy, which aims to inhibit the evolutionary dynamics governing the spread of resistant tumor phenotypes. Adaptive therapy changes focus from the cancer cells that are responsive to therapy to those that are resistant and ultimately govern outcome. This therapeutic approach retains a pool of sensitive cancer cells to compete with the therapy-resistant ones through dynamic dose modulation and/or timing. Thus, fluctuations of treatment-sensitive cells are used to control the resistant population and prolong tumor control with existing therapy agents. Here, we explore non-genetic mechanisms of resistance, including the protective role of the tumor stroma, the epithelial-to-mesenchymal transition, the overexpression of drug efflux pumps, and the extracellular vesicle-mediated transfer of them. These mechanisms can increase the size of the resistant population at the expense of the sensitive one, reducing the ability of adaptive therapy to force tumor evolution into controllable cycles.</p>