Tumor progression relies upon the dynamic interaction of cancer cells with host fibroblasts, endothelial cells, immune cells and components of the extracellular matrix, collectively known as the tumor microenvironment. Despite this, relatively little is known about how normal host cells dictate the response of tumors to anti-cancer therapies. Emerging data suggests that host factors play a critical role in determining risks for tumor progression and decreased therapeutic responses. In particular, recent findings have provided evidence that the tumor microenvironment provides a protective niche that allows minor populations of cancer cells to escape from the cytotoxic effects of radiation, chemotherapy and targeted therapies. In this review we will outline the mechanisms by which tumor cells and host fibroblasts co-operate to drive tumor initiation and progression. In particular, we will focus upon the mechanisms by which tumor cells exposed to targeted therapies co-opt the host leading to therapeutic escape and resistance. We will end by discussing the idea that long-term responses to targeted anticancer therapies will only be achieved through strategies that target both the tumor and host.