People routinely hear and understand speech at rates of 120–200 words per minute [1, 2]. Thus, speech comprehension must involve rapid, online neural mechanisms that process words’ meanings in an approximately time-locked fashion. However, in the context of continuous speech, electrophysiological evidence for such time-locked processing has been lacking. Whilst valuable insights into the semantic processing of speech have been provided by the “N400 component” of the event-related potential [3-6], this literature has been dominated by paradigms using incongruous words within specially constructed sentences, and may not accurately reflect natural, narrative speech comprehension. Building on the discovery that cortical activity “tracks” the dynamics of running speech [7-9], and psycholinguistic work both demonstrating [10-12] and modeling [13-15] how context rapidly impacts on word processing, we describe a new approach for deriving an electrophysiological correlate of natural speech comprehension. We used a computational model [16] to quantify the meaning carried by each word based on how semantically dissimilar it was to its preceding context and then regressed this quantity against electroencephalographic (EEG) data recorded from subjects as they listened to narrative speech. This produced a prominent negativity at a time-lag of 200–600 ms on centro-parietal EEG channels, characteristics common to the N400. Applying this approach to EEG datasets involving time-reversed speech, cocktail party attention and audiovisual speech-in-noise demonstrated that this response was very sensitive to whether or not subjects understood the speech they heard. These findings demonstrate that, when successfully comprehending natural speech, the human brain responds to the contextual semantic content of each word in a relatively time-locked fashion.