The refinement of large, crowded and asymmetric systems has always proved highly challenging using gas-phase electron diffraction (GED) data. Frequently, local symmetry constraints are still applied to the system to ensure a manageable size of parameter set during the refinement process. This can lead to errors in the heavyatom structure, as the core atoms move to compensate for the artificially enforced constraints on the peripheral atoms. This work is focused on the development of the new Structure Enhancement Methodology using Theory and Experiment (SEMTEX) method, which enables the incorporation of high-level ab initio data dynamically throughout the refinement process. Initially, the bulky phosphine molecules OPBul₃ and HNPBul₃ were studied to test the method, since a ready comparison could be made to previous studies. Subsequent work has seen the technique applied to various different structures. The fluorinated ring compound C₆F₁₁CF₃ has been studied, where the peripheral fluorine atoms can be expected to make a large contribution to the overall scattering. The refinement of the structure of the tungsten compound W(NBuᵗ)₂(NHBuᵗ)₂ followed, presenting a test case for the new method in which more than one conformer was present. The technique was then applied to the family of compounds C(SiMe₃Cl)₄, C(SiMe₃Br)₄ and C(SiMe₃F)₄, large, bulky molecules with more than one type of peripheral atom in the same structure and several conformers present in significant quantity. Finally, the GED refinement of the structure of Fe₃(CO)₁₂i s reported, a case where the new method must be further developed in order to be applicable.