Language comprehension requires the rapid retrieval and integration of contextually appropriate concepts (“semantic cognition”). Current neurobiological models of semantic cognition are limited by the spatial and temporal restrictions of single-modality neuroimaging and lesion approaches. This is a major impediment given the rapid sequence of processing steps that have to be coordinated to accurately comprehend language. Through the use of fused functional magnetic resonance imaging and electroencephalography analysis in humans (n= 26 adults; 15 females), we elucidate a temporally and spatially specific neurobiological model for real-time semantic cognition. We find that semantic cognition in the context of language comprehension is supported by trade-offs between widespread neural networks over the course of milliseconds. Incorporation of spatial and temporal characteristics, as well as behavioral measures, provide convergent evidence for the following progression: a hippocampal/anterior temporal phonological semantic retrieval network (peaking at ∼300 ms after the sentence final word); a frontotemporal thematic semantic network (∼400 ms); a hippocampal memory update network (∼500 ms); an inferior frontal semantic syntactic reappraisal network (∼600 ms); and nodes of the default mode network associated with conceptual coherence (∼750 ms). Additionally, in typical adults, mediatory relationships among these networks are significantly predictive of language comprehension ability. These findings provide a conceptual and methodological framework for the examination of speech and language disorders, with additional implications for the characterization of cognitive processes and clinical populations in other cognitive domains.SIGNIFICANCE STATEMENTThe present study identifies a real-time neurobiological model of the meaning processes required during language comprehension (i.e., “semantic cognition”). Using a novel application of fused magnetic resonance imaging and electroencephalography in humans, we found that semantic cognition during language comprehension is supported by a rapid progression of widespread neural networks related to meaning, meaning integration, memory, reappraisal, and conceptual cohesion. Relationships among these systems were predictive of individuals' language comprehension efficiency. Our findings are the first to use fused neuroimaging analysis to elucidate language processes. In so doing, this study provides a new conceptual and methodological framework in which to characterize language processes and guide the treatment of speech and language deficits/disorders.