It is a current idea that carcinogenesis as well as tumor progression are dynamic processes, which involve inherited as well as somatic mutations and include a continuing adaptation to different microenvironmental conditions. There is, in fact, rising evidence that tumor cells are under a persistent stress and that autocrine as well as microenvironment-derived survival factors play a substantial role for the final outcome of the tumor development as well as for response to the anti-tumor therapy. We will review current achievements on the molecular biology of the microenvironment-derived survival signaling and therapeutical approaches, which are presently under clinical development. By the use of plasma cell disorders as an outstanding clinical model, we will discuss the development of novel in vivo preclinical models which recapitulate the human bone marrow milieu. Finally, we will discuss several topics which appear to be relevant for a successful clinical translation of preclinical research in this specific field.