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The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. In the case of microenvironment-mediated resistance this can involve an intrinsic response, including the co-option of pre-existing structural elements and signaling networks, or an acquired response of the tumor stroma following the therapeutic insult. Alternatively, in other contexts, the TME has a multifaceted ability to enhance therapeutic efficacy. This review examines recent advances in our understanding of the contribution of the TME during cancer therapy and discusses key concepts that may be amenable to therapeutic intervention.