Combination of conventional chemotherapy with compounds that selectively enhance the sensitivity of tumors to DNA damaging agents is a very attractive strategy for anticancer therapy. The prerequisites are, of course, (1) a deeper understanding of the basic mechanisms that protect tumor cells from DNA damaging agents and (2) pharmacological options to modulate these mechanisms. In our projects we follow two major paths to reach these aims: One is to investigate the prerequisites of sensitivity to DNA damaging agents in chemo-sensitive tumors which should help us to understand the alterations of DNA damage response pathways in less sensitive tumor cells. The final goal is then to pharmacologically manipulate those pathways in a way that renders tumors hypersensitive to chemotherapy. The other path focuses on the role of cancer-associated fibroblasts (CAFs) for sensitivity of the tumor to chemotherapy. It is a well established phenomenon that these modified and activated fibroblasts possess permissive and promoting properties for tumor cells. We therefore established a collection of CAFs from individual lung and breast tumors, now consisting of more than 100 well characterized CAF strains, which can be used for single culture as well as for co-culture experiments together with tumor cells. The goal is to identify pharmacological options to manipulate the CAFs in a way that they lose their tumor protecting properties.