Conjugated polymers provide a unique toolbox for establishing electrical communication with biological systems. In this talk, I will show how modulating the chemistry of these materials can lead to interfaces that maximize interactions with biological systems while maintaining electronic transport properties. These materials are then used in organic electrochemical transistors (OECTs) to detect biological species in physiological media. I will introduce two types of OECT based sensors; one that detects metabolites with performance exceeding the state-of-the-art, and the other that detects coronavirus spike proteins at the physical limit. Having challenged these sensors with patient samples and cellular media, I will discuss areas where proof-of-concept platforms may fail and how to prolong the operation in biological environments. By tackling each of these problems, we improve device performance to a level that marks a considerable step toward label-free diagnostics.