A three-pronged approach has been used to design rational improvements in self-assembled monolayer field-effect transistors: classical molecular dynamics (MD) simulations to investigate atomistic structure, large-scale quantum mechanical (QM) calculations for electronic properties, and device fabrication and characterization as the ultimate goal. The MD simulations reveal the effect of using two-component monolayers to achieve intact dielectric insulating layers and a well-defined semiconductor channel. The QM calculations identify improved conduction paths in the monolayers that consist of an optimum mixing ratio of the components. These results have been used both to confirm the predictions of the calculations and to optimize real devices. Monolayers were characterized with X-ray reflectivity measurements and by electronic characterization of complete devices.