Interfacial molecular recognition processes can be converted into mechanical responses via modulation of surface stress. We demonstrate dramatic enhancement in this transduction when quasi 3-D interfaces with nano-size features are used. Microcantelever surfaces are modified with gold nanospheres or granular films and functionalized with macrocycle cavity and receptors. Deflections of these nanostructured cantilevers in response to vapor phase hydrocarbons are two orders of magnitude larger than with conventional smooth surfaces. Such a significant enhancements of surface stress changes resulting from intermolecular interactions at vapor- and liquid-solid interfaces offer an attractive means to develop novel nano-mechanical devices that respond directly and sensitively to chemical stimuli.