Organic electrochemical transistors (OECTs) are electronic devices relying on electronic materials that are stable in aqueous environments. OECTs leverage ionic solutions for their operation, so OECTs are well-suited for interfacing with biological systems for electrophysiology and biochemical sensing, in particular, in point-of-care diagnostics, wearable and implantable technologies, and in organ-on-chip systems. The interface of OECTs with biological systems is a crucial parameter that determines the function and performance of the devices, influencing the design criteria, including the selection of materials and device form factor, geometry and architecture. The selected design features must enable seamless interaction with biological components while ensuring reliable and stable device performance in complex settings. In this Review, we investigate the biological interfaces of OECT-based biosensors, examining their complexity and length scale. We highlight interface designs with biomolecules, such as lipids, proteins and aptamers, as well as in vitro cell culture and the human body. Importantly, we explore strategies to improve each interface type and identify gaps in our current understanding that warrant further investigation.