Nearly all existing nanoelectronic sensors are based on charge detection, where molecular binding changes the charge density of the sensor and leads to sensing signal. However, there are several fundamental limitations to the charge-detection based electronic sensors. The examples include the ionic screening effect in high ionic strength solution, and the sensitivity-speed tradeoff for vapor phase sensing. In this talk, I will discuss our group’s recent works on a new paradigm of electronic sensing by exploring the heterodyne mixing response between the molecular dipole and a nanoscale transistor. First, we successfully demonstrated that the fundamental ionic screening effect can be mitigated by operating single-walled carbon nanotube field effect transistor as a high-frequency heterodyne biosensor. Electrical detection of streptavidin binding to biotin in 100 mM buffer solution is achieved at a frequency beyond 1 MHz. The results should promise a new biosensing platform for point-of-care detection, where biosensors functioning directly in physiologically relevant condition are desired. Second, we demonstrated the concept of nanoelectronic heterodyne sensor for vapor detection in a graphene device. The dipole detection mechanism is confirmed by a plethora of experiments with vapor molecules of various dipole moments, particularly, with cis- and trans-isomers that have different polarities. Rapid (down to 0.1 s) and sensitive (down to 1 ppb) detection of a wide range of vapor analytes is achieved, representing orders of magnitude improvement over state-of-the-art nanoelectronics sensors. Finally, we demonstrated electrical probing and tuning of the non-covalent physisorption of polar molecules on graphene surface by using graphene nanoelectronic heterodyne sensors. Our results provide insight into small molecule-nanomaterial interaction dynamics and signify the ability to electrically tailor interactions, which can lead to rational designs of complex chemical processes for catalysis and drug discovery.