Fundamental physics began the twentieth century with the twin revolutions of relativity and quantum mechanics, and much of the second half of the century was devoted to the construction of a theoretical structure unifying these radical ideas. But this foundation has also led us to a number of paradoxes in our understanding of nature. Attempts to make sense of quantum mechanics and gravity at the smallest distance scales lead inexorably to the conclusion that space-time is an approximate notion that must emerge from more primitive building blocks. Furthermore, violent short-distance quantum fluctuations in the vacuum seem to make the existence of a macroscopic world wildly implausible, and yet we live comfortably in a huge universe. What, if anything, tames these fluctuations? Why is there a macroscopic universe? These are two of the central theoretical challenges of fundamental physics in the twenty-first century. In this essay, I describe the circle of ideas surrounding these questions, as well as some of the theoretical and experimental fronts on which they are being attacked.