Throughout cancer progression, metastasis and chemotherapeutic resistance are largely responsible for poor patient prognosis, and importantly, for cancer-related deaths. Cancer cells must evade cell death signaling induced during the metastatic cascade, a process involving detachment from the extracellular matrix (ECM) or interaction with foreign matrix environments, as well as the cell death induced by exposure to chemotherapy to enable their survival. In recent years our understanding of how cancer cells survive during these processes has improved. However, it is imperative that we expand our knowledge of the signaling that takes place during cancer progression in order to provide improved therapeutic options for elimination of these cells. Here, we detail a novel mechanism whereby carcinoma-associated fibroblasts (CAFs) secrete insulin-like growth factor binding proteins (IGFBPs) into the tumor microenvironment that trigger the ultimate survival of cancer cells during ECM-detachment. We have found the presence of secreted IGFBP-2 and -5 elicits a downstream protein-signaling cascade that results in the stability of Mcl-1, an anti-apoptotic protein, ultimately promoting the ability of cancer cells to elude ECM-detachment induced apoptosis, or anoikis. These data are the first to describe a specific contribution from the tumor microenvironment in the evasion of anoikis. With enhanced appreciation for the contributions of the tumor microenvironment to cancer cell survival and disease progression, it is imperative that we consider cell types such as CAFs in our treatment regimen for patients. The data provided here present the opportunity for IGFBP-2 and -5 to be potential chemotherapeutic targets to improve the current standard lines of care.In parallel to our studies understanding the contribution of CAFs to cancer cell survival and disease progression, we have also started exploring normal microenvironment fibroblasts (NMFs). Currently the notion of normal microenvironment suppression of disease progression is a relatively unexplored area. However, our early evidence expands upon these data and suggests NMFs are capable of impairing the ability of cancer cells to survive in the presence of secreted factors from NMFs. It is critical that we continue this line of investigation as it may present the opportunity to use physiologically relevant secreted factors to sequester cancer cell survival. Finally, in addition to identifying novel chemotherapeutic targets, here we also explain the engineering and testing of a novel immunotoxin. Immunotoxins are chimeric proteins comprised of a targeting ligand conjugated to a toxin domain. Our efforts have been focused on eliminating the opportunity for chemotherapy resistance. Hence, our immunotoxin uniquely acts at the cell surface, thereby preventing the need for internalization previous compounds require and theoretically overcoming this opportunity to become resistant. Lastly, we also show a novel genetic engineering strategy that allows for easily amenable protein production to adapt the compound for screening innumerous targets and toxicity variations. Further development of our immunotoxin could provide promise for a new chemotherapy option with diverse application prospects.