To date, the majority of published works on electronic and optoelectronic properties of 2D materials has been from mechanically exfoliated flakes on silicon oxide. However, if we are to make 2D materials a viable material technology, we must be able to grow them over very large scale, with exceptional control over structure, chemistry, and doping. We have demonstrated that direct synthesis of a variety of 2D layers and heterostructures, and have found that the substrate upon which the materials are grown can ultimately dictate the properties and performance of the synthetic layers. In this talk, I will discuss recent breakthroughs in our understanding and engineering of the 2D/3D interface to achieve high quality 2D layers on sapphire and other crystalline substrates. This includes the impact of substrate chemistry, structure, and defects on achieving high moblity and high quantum-yield 2D layers.