Over the past decade, researchers in computational chemistry have witnessed a resurgence in the development and application of semi-empirical methods for treating large chemical/material systems. In particular, the density functional tight binding (DFTB) formalism has garnered immense popularity for probing the electronic properties of biomolecules, 5 molecules/clusters with numerous conformations, and immense nanostructures. While classical molecular dynamics can handle hundreds of thousands of atoms, it cannot provide a first-principles-based description of large systems at a quantum mechanical (i.e., electronic) level of detail. At the other extreme, conventional Kohn-Sham density functional theory (DFT) methods can access the true quantum mechanical nature of matter, but they cannot tackle the large sizes and complex chemical environments relevant to many of the large systems mentioned previously. To bridge these immense size scales, the DFTB formalism was developed to probe these chemical/materials systems with a viable approach that is both computationally efficient and quantum mechanical in nature.