The recent advent of X-ray free-electron lasers (XFELs) marks the beginning of a new era in X-ray science, providing coherent ultrafast X-ray pulses with unprecedented peak brightness. The first generation of these facilities (FLASH, LCLS, and SACLA) have already had tremendous scientific impact, and numerous similar facilities are now being developed around the world. These first-generation XFELs are based on pulsed-radio frequency (RF) accelerator technology with limited repetition rates. Thus, they provide only modest average brightness, comparable to or lower than that available from existing storage rings, and this limits their impact in key areas of science. A new generation of XFELs is now under development, exploiting continuous-wave RF superconducting accelerator technology (CW-SCRF) to provide ultrafast X-ray pulses up to MHz repetition rates in a uniform or programmable time structure. This chapter highlights some compelling new science opportunities that will be enabled by such high-repetition-rate XFELs. These opportunities have been identified and developed through numerous workshops over the past decade. In February 2015, a series of workshops were held at SLAC focusing on the new science opportunities that will be enabled by LCLS-II, which will provide ultrafast X-rays in the 0.25–5 keV range at repetition rates up to 1 MHz.