In this chapter, an analytical analysis of a new graphene-based sensor called Dielectric Modulated Graphene Field Effect Transistor (DMG-FET), for high-performance biomolecule sensing applications, is developed and established by experimental validation. The challenges to develop analytical and compact models to investigate the graphene-based devices for biomolecule sensing applications are presented in this chapter. In this context, analytical expressions of the subthreshold drain current through the use of a good approximation is illustrated, and the sensitivity of conventional FETbased sensors is improved. An analytical analysis comprising biomolecule concentration effect, drain current, threshold voltage shift and sensitivity behavior for DMG-FET are developed, in which the drift-diffusion transport mechanism is used to get accurate analytical models for investigating the DMG-FET behavior. The sensitivity of the proposed design is compared with that of conventional FET-based sensors. Due to the high performance provided by the proposed sensor, the read of the biomolecule concentrations is carried out by using an appropriate Read-out Circuit, which is suitable for practical low power applications. It is to note that the proposed sensor has better electrical and scaling performance in comparison with the conventional design. This result makes the proposed design as a promising candidate to serve as a highly sensitive low-power and reliable graphene-based sensing applications. For that reason, the dielectric-modulated Graphene FET (DMGFET) provides a practical approach towards biomolecule detection that could be extended to other applications.