The rise of organic bioelectronics efficiently bridges the gap between semiconductor devices and biological systems, leading to flexible, lightweight, and low-cost organic bioelectronic devices suitable for health or body signal monitoring. The introduction of organic semiconductors in the devices can soften the boundaries between microelectronic systems and dynamically active cells and tissues. Therefore, organic bioelectronics has attracted much attention recently due to the unique properties and promising applications. Organic thin film transistors (OTFTs), owing to their inherent capability of amplifying received signals, have emerged as one of the state-of-the-art biosensing platforms. The advantages of organic semiconductors in terms of synthetic freedom, low temperature solution processing, biocompatibility, and mechanical flexibility render OTFTs ideal transducers for wearable electronics, e-skin, and implantable devices. How to realize highly sensitive, selective, rapid, and efficient signal capture and extraction of biological recognition events is the major challenge in the design of biosensors. OTFTs are prone to converting the presence or change of target analytes into specific electrical signals even in complex biological systems. More importantly, OTFT sensors can be conveniently functionalized with chemical or biological modifications and exhibit substantially improved device sensitivity and selectivity as well as other analytical figure of merits, including calibration range, linearity, and accuracy. However, the stability and reproducibility of the organic devices need to be further improved. In this Account, we first introduce the unique features of OTFTs for bioelectronic applications. Two typical OTFT configurations, including organic electrochemical transistor (OECT) and electrolyte gated organic field effect transistor (EGOFET), are highlighted in their sensing applications mainly due to the operation of the devices in electrolytes and the combination of ionic and electronic charge transports in the devices. These devices are potentiometric transducers with low working voltages (<1 V) and high sensitivity, and are thus suitable for wearable applications with low power consumption. Second, the functionalization strategies on channel materials, electrolytes, and gate electrodes based on various modification methods and sensing mechanisms are discussed in sequence. In an OECT- or EGOFET-based biosensor, the device performance is particularly sensitive to the physical properties of the two interfaces, including channel/electrolyte and gate/electrolyte interfaces. Any change in the potential drop or capacitance of either interface can influence the channel current substantially. Therefore, the functionalization of the interfaces is critical to the sensing performance. In particular, when an electrochemically active material is modified on the interfaces, the reaction of the analyte catalyzed by the modified material can influence the interface potential and lead to a channel current response much stronger than that of a conventional electrochemical measurement. So the biosensors are much more sensitive than typical analytical methods due to the signal amplification of the transistors. Third, the processing techniques including screen printing and inkjet printing and the possibility for mass production are discussed. The applications of organic transistors in wearable electronics and healthcare monitoring systems, especially the fabric OECT-based biosensors for noninvasive detection, are presented. It is expected that the versatile organic transistors will enable various compact, flexible and disposable biosensors compatible with wearable electronics.