Organic-inorganic hybrid gas sensors can offer outstanding performance in terms of selectivity and sensitivity towards single gas species. The enormous variety of organic functionalities enables novel flexibility of active sensor surfaces compared to commonly used pure inorganic materials, but goes along with an increase of system complexity that usually hinders a predictable sensor design. In this work, an ultra-selective NO2 sensor is realized based on self-assembled monolayer (SAM)-modified semiconductor nanowires (NWs). The crucial chemical and electronic parameters for an effective interaction between the sensor and different gas species are identified using density functional theory simulations. The theoretical findings are consistent with the experimentally observed extraordinary selectivity and sensitivity of the amine-terminated SnO2 NW towards NO2. The energetic position of the SAM-gas frontier orbitals with respect to the NW Fermi level is the key to ensure or impede an efficient charge transfer between the NW and the gas. As this condition strongly depends on the gas species and the sensor system, these insights into the charge transfer mechanisms can have a substantial impact on the development of highly selective hybrid gas sensors.