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In this essay, we reflect on two fundamental assumptions, the one philosophical and the other scientific. The first has been called the Principle of Sufficient Reason (PSR). This encapsulates the idea that there is (at least in principle) a complete explanation for everything that exists or happens. We argue that recent attempts in philosophy to undermine the PSR should be rejected on a combination of philosophical and scientific grounds, and PSR should be upheld. Secondly, we argue, from the assumption that PSR is true, that the quantum vacuum (QV) is not the most fundamental stuff that exists, and moreover that we can say something positive about the nature of the “more fundamental” stuff. We argue that these conclusions follow from the implications that PSR carries for the nature of scientific explanations applied within the framework of the model of Nature indicated by Systems Philosophy. We show that under PSR the indicated substance underlying the QV has promise for developing solutions to certain fundamental empirical puzzles in science such as the nature of dark energy and the foundations of consciousness.