Quantum computing sits poised at the verge of a revolution. Quantum machines may soon be capable of performing calculations in chemistry, physics, and other fields that are extremely difficult or even impossible for today’s computers. The multi-institutional Enabling Practical-scale Quantum Computing (EPiQC) Expedition will help bring the great potential of this new paradigm into reality by reducing the current gap between existing theoretical algorithms and practical quantum computing architectures. Over five years, the EPiQC Expedition will collectively develop new algorithms, software, and machine designs tailored to key properties of quantum device technologies with 100 to 1000 quantum bits. This work will facilitate profound new scientific discoveries and also broadly impact the state of high-performance computing.