Fundamental physics started the 20th 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. Yet storm clouds are gathering, which point towards a new set of revolutions on the horizon in the 21st century. Space-time is doomed—how can it emerge from more primitive building blocks? And how is our macroscopic universe compatible with violent microscopic quantum fluctuations that seem to make its existence wildly implausible? In this talk I will describe these deep mysteries and outline some of our strategies for making progress on them. I will also discuss plans for a giant new particle accelerator with energy seven times higher than the Large Hadron Collider that will be necessary to make major progress on at least some of these questions in the coming decades.