Nanowire field effect transistors (NWFETs) are emerging as powerful tools for biological applications such as bio-molecule detection, yet their sensitivity limits are not understood at a fundamental level. I will discuss the interplay of device parameters such as gate bias and NW diameter on the operating modality and sensitivity of NWFET sensors. pH and cancer marker detections are studied as silicon-NWFETs are tuned from linear to subthreshold regimes by electrochemical gating. First, pH sensing data show that NWFET has the strongest response and the best signal to noise ratio in the subthreshold regime. Operating in the subthreshold regime also reduces the detection limit for prostate specific antigen down to ~fM for a device with ~pM detection limit in the linear regime. This sensitivity improvement is due to the reduced screening ability of carriers in NW. A quantitative model describing these results and the intrinsic charge detection limit of NWFET sensors will be discussed.