Lorenz Poellinger was a leader in understanding the effects of altered microenvironmental conditions in tumor biology and in normal physiology. His work examining the effects of hypoxia and the HIF transcription factors has expanded our understanding of the role of the microenvironment in affecting the behaviour of both normal and malignant cells. Furthermore, his work provides a model for understanding the adaptive responses to other metabolic stress conditions. By investigating the molecular mechanisms responsible for the adaptive responses to metabolic stress in normal physiological situations, across pathological conditions, and in different model organisms, his work shows the power of combining data from different model systems and physiological contexts. In cancers, it has become clear that in order to evolve to become an aggressive malignant disease, tumor cells must acquire the capacity to tolerate a host of abnormal and stressful metabolic conditions. This metabolic stress can be thought of as a fire that tumor cells must douse with enough water to survive, and may offer opportunities to exploit smoldering vulnerabilities in order to eradicate malignant cells.