Several two-dimensional (2D) materials have been synthesized experimentally, but many theoretically predicted 2D materials are yet to be synthesized. Here, we will review a density-functional theory based framework to enable high-throughput screening of suitable substrates for the stabilization and functionalization of 2D layers. A Materials Project based open source python tool, MPInterfaces, based on this framework, is being developed to automate the search of suitable substrates as well as to characterize their effect on the structural and electronic properties of 2D materials. Lattice-matching, symmetry-matching, substrate surface termination, configuration sampling, substrate induced structural distortion and doping estimation algorithms are being developed and will be described in this article. This computational tool will be employed to identify suitable substrates for scores of technologically relevant 2D materials, leading to acceleration of their synthesis and application, and more efficient use of experimental resources.