Electrical biosensors based on graphene field-effect transistors (GFETs) have shown great potential for rapid and highly sensitive detection of a wide range of biomolecules. Biosensors based on GFETs have the potential to enable the development of point-of-care diagnostic tools for early-stage disease detection. They are biocompatible, easy to functionalize, scalable for mass production, and can be incorporated into portable devices for point-of-care diagnostics. However, sensitivity and selectivity are paramount for biomolecule detection in complex physiological solutions. Issues with reproducibility and uniformity of graphene sensors, but also with Debye screening and unwanted detection of non-specific species, have prevented the wider clinical use of graphene technology. This thesis attempts to addresses the critical challenges related to the performance limitations of GFETs in clinical settings, including sensitivity and selectivity. This thesis introduces strategies to enhance the performance and increase the accuracy of GFETs biosensors detection of disease biomarkers in complex physiological solutions.