We demonstrate how substrate interfacial chemistry can be utilized to tailor the physical properties of single-crystalline molybdenum disulfide (MoS2) atomic-layers. Semiconducting, two-dimensional MoS2 possesses unique properties that are promising for future optical and electrical applications for which the ability to tune its physical properties is essential. We use self-assembled monolayers with a variety of end termination chemistries to functionalize substrates and systematically study their influence on the physical properties of MoS2. Using electrical transport measurements, temperature-dependent photoluminescence spectroscopy, and empirical and first-principles calculations, we explore the possible mechanisms involved. Our data shows that combined interface-related effects of charge transfer, built-in molecular polarities, varied densities of defects, and remote interfacial phonons strongly modify the electrical and optical properties of MoS2. These findings can be used to effectively enhance or modulate the conductivity, field-effect mobility, and photoluminescence in MoS2 monolayers, illustrating an approach for local and universal property modulations in two-dimensional atomic-layers.