The macro and microenvironments within which malignant neoplasms arise can exert profound influences on tumor behaviors that range from a complete reversion of the malignant phenotype to the promotion of tumor cell invasion and metastatic growth. In addition to tumor cells, the architecture of most solid tumors includes an assortment of non-malignant cell types derived from distinct developmental lineages that carry out structural or functional roles including fibroblasts, muscle cells, nerves, and vasculature. We have determined that components of tumor microenvironments (TME) also contribute to de novo and acquired treatment resistance. In current practice, the majority of cancer-directed therapeutics do not exclusively target malignant cells, but also injure benign cells in the local, and potentially the distant host microenvironments. Such collateral damage is quite evident for non-specific therapies that involve DNA-damaging modalities such as genotoxic drugs and ionizing radiation. Ongoing work centers on characterizing a DNA Damage Secretory Program in the TME that is comprised of a remarkable spectrum of proteases, growth factors and cytokines. The composite effects of this program promote tumor cell proliferation, invasion, metastasis, and also enhance resistance to therapeutics.