The fabrication of wafer-scale two-dimensional (2D) materials is a prerequisite and important step for their industrial applications. Chemical vapor deposition (CVD) is the most promising approach to produce high-quality films in a scalable way. Recent breakthroughs in the epitaxy of wafer-scale single-crystalline graphene, hexagonal boron nitride, and transition-metal dichalcogenides highlight the pivotal roles of substrate engineering by lattice orientation, surface steps, and energy considerations. This review focuses on the existing strategies and underlying mechanisms, and discusses future directions in epitaxial substrate engineering to deliver wafer-scale 2D materials for integrated electronics and photonics.