The focus of our studies is to understand how cancer cells communicate within their hostile microenvironment during tumor development. The ultimate goal is to identify novel biomarkers and more rational treatment strategies of the most aggressive, therapy resistant tumors. Based on previous findings we explore the hypothesis that transport vesicles (exosomes and endosomes) promote tumor aggressiveness and constitute therapeutic targets specifically related to typical features of the tumor microenvironment. We use advanced experimental models at the cellular level in conjunction with patient samples and clinical trials to unravel how cancer cells adapt to intrinsic stress factors, such as hypoxia and acidosis. Our concept of taking advantage of specific tumor microenvironment characteristics in combination with a unique strategy for the identification of cancer cell target proteins has potential to provide new treatment concepts and diagnostic tools to the benefit for cancer patients.