Hsp70 is the central component of a multi-chaperone machine involved in many essential cellular processes and in the response of cells to proteotoxic stresses (e.g. heat shock). Furthermore, Hsp70 is a potent anti-apoptotic protein that can enhance transformation and the tumorigenic potential of cells. This proposal aims to obtain detailed knowledge of the function of the Hsp70 machine and its regulation by co-chaperones. This knowledge will be used to gain insight in its exact role in disease pathogenesis with special emphasis on cancer. The results are expected to reveal new possibilities for therapeutic interventions. The knowledge obtained will, furthermore, be exploited to improve the industrial use of mammalian cells as protein factories by attacking major problems in the large- scale production of therapeutic proteins in mammalian cells, i.e. increased apoptosis, sensitivity to temperature shifts, and incomplete protein folding.