Charge based detection of bio-analytes using field-effect-transistors (FET's) presents an attractive route towards realizing low cost, ultrasensitive and label-free electronic biosensors. The first realization of such a biosensor was based on the Ion-Sensitive Field Effect Transistor (ISFET), developed by Piet Bergveld and has been instrumental in inspiring many FET based bio-sensor designs and concepts. This thesis takes inspiration from the ISFET, builds on well understood CMOS technology, integrates neuromorphic style operation and flash memory principles to realize floating-gate ISFET's capable of charge sensing, simultaneous ionic actuation and colocalized impedance spectroscopy based detection. The device termed the Chemoreceptive Neuron MOS Transistor (C[nu]MOS) is theoretically and experimentally investigated for both biomolecular sensing and secretory analysis from cells. Chapter 1 describes a brief background to the field of ISFET based biosensing. The relative merits and challenges associated with FET based biosensing are discussed. Chapter 2 describes the sensor structure, tunneling operation and interface physics under study in this dissertation. The structure takes inspiration from multi-input floating gate memories. The interface between the transistor and the fluid is modeled incorporating effects such as surface equilibrium constants and ion size. Actuation by non-volatile charge injection is introduced and is shown to tune the pH sensitivity thus realizing a single transistor sensor-actuator hybrid. Multivalent ion induced corelations such as charge inversion is described. Chapter 3 describes the device as a DNA sensor. Physics of the DNA-transistor interface is presented. Electric field induced DNA desorption and refreshabilty is discussed. Impedance spectroscopy using split signal delivery is outlined. Chapter 4 outlines factors that affect DNA detection, role of background electrolyte composition, surface properties and methods to improve sensitivity at the transistor interface. Chapter 5 introduces the use of split signal delivery and impedance spectroscopy for ultrasensitive pathogenic DNA detection. SPICE simulations depict dominant poles and zeros in the system and their relative dependence on analyte properties. The use of branched Y-DNA motifs and target induced self-assembly are introduced as signal amplification mechanisms pushing the limits of target detection down to ~100fM on CMOS. Chapter 6 describes the coupling between excitable chromaffin cells and non-excitable RBL-2H3 mast cells with floating gate transistors. The mechanisms of electrochemical and electrical activity detection are discussed. Simultaneous charge and impedance sensing is introduced. Chapter 7 presents the conclusion and future outlook.