Abstract: In an effort to improve the predictive power and transferability of semi-empirical Hamiltonians as well as to extend the size-scales involved in quantum-mechanics based simulations, we have developed a robust parameterized Hamiltonian (SCED-LCAO) that can predict the structure and electronic properties of complex materials of 10nm-15nm size. A successful model for a semi-empirical Hamiltonian must capture charge redistributions and electron screening in a many-body environment so that bond-breaking and bond-forming processes associated with complex structural reconstructions can be described appropriately. The SCED-LCAO Hamiltonian, based on a linear combination of atomic orbitals (LCAO) framework, has been designed to capture these important processes through environment-dependent (ED) multi-center terms and through charge self-consistency (SC) in the calculation of energy and forces. Additionally, the framework of the SCED-LCAO Hamiltonian allows for charge self-consistency (SC) and environment-dependency (ED) to be treated on the same footing. The SCED-LCAO Hamiltonian has been developed for silicon, germanium, carbon, boron, phosphorous, and nitrogen using an extensive database of properties obtained from first-principles. Boron-based systems are notorious because of its chemical complexity and the success of the SCED-LCAO Hamiltonian in this case is a testament to the robustness of this Hamiltonian to different atomic environments. The success of the SCED-LCAO Hamiltonian will be elucidated through the following applications: (i) the phase transformations of carbon bucky-diamond cluster upon annealing, (ii) the discovery of bucky-diamond SiC clusters, (iii) the morphology and energetics of SiC nanowires (NWs), and (iv) the initial stage of growth of single-wall carbon nanotubes (SWCNTs).