Studying semantic processing during language comprehension in humans at the single-cellular level Humans are capable of communicating extraordinarily rich and nuanced meanings through language. This capacity surpasses that of all other animal species. Yet, despite a growing understanding of the network of brain areas that supports semantic processing, the precise derivation of linguistic meaning in neural tissue at the cellular-level and over the temporal scales of action potentials remains largely unknown. Over the past several years, our collaborative group has developed unique approaches that have allowed us to record from individual neurons in the language-dominant prefrontal and temporal cortex in participants performing structured linguistic tasks. Here, we will use this extraordinarily rare opportunity together with our group’s unique combined expertise in linguistic theory, human intraoperative neurophysiology, single-neuronal recordings and computational modeling in order to study in detail, for the first time, how semantic information is encoded at a cellular-level during speech and the degree to which single neurons respond selectivity to specific semantic domains, whether semantic information can be robustly decoded from neural activity, the extent to which it can be generalized across linguistic materials and the process by which these neuronal activities maps onto the fine-grained semantic relationships between individual words. Using structured linguistic manipulations and violations and by employing information-theoretic techniques, we will also crucially examine whether certain neurons in humans respond selectively to linguistic compared to non-linguistic information, how they engaged in lexico-semantic or syntactic processes, how they track the real-time context-dependent inferred meanings of individual words during speech and how these mixed representations and computations are distributed within frontal and temporal cortical populations in the language-dominant hemisphere. Taken together, this novel cross-institutional, inter-disciplinary collaborative effort promises to provide a fundamental new platform by which to begin studying the basic cellular mechanisms that underlie human language and unprecedented new insight into the cellular-level processing and representation of linguistic meaning during language comprehension in humans.