The ability to sense and adapt to low oxygen levels (hypoxia) is central for most organisms and cell types. At the center of this process is a molecular mechanism, the cellular hypoxic response, in which the hypoxia inducible factors (HIFs) are stabilized by hypoxia, allowing the HIF proteins to act as master transcriptional regulators to adjust the cell to a low oxygen environment. In recent years, it has become increasingly appreciated that the cellular hypoxic response does not always operate in splendid isolation, but intersects with signaling mechanisms such as Notch signaling, a key regulatory signaling mechanism operating in most cell types controlling stem cell maintenance and differentiation. In this review, which is dedicated to the memory of Lorenz Poellinger,1 we discuss how the intersection between Notch and the cellular hypoxic response was discovered and our current understanding of the molecular basis for the cross-talk. We also provide examples of where Notch and hypoxia intersect in various physiological and disease contexts.