Individual cells need to discern and synchronize transcriptional responses according to variations in external and internal conditions. Metabolites and chemical compounds are sensed by transcription factors (TFs), which direct the corresponding specific transcriptional responses. We propose a classification of the currently known TFs of Escherichia coli based on whether they respond to metabolites incorporated from the exterior, to internally produced compounds, or to both. When analyzing the mutual interactions of TFs, the dominant role of internal signal sensing becomes apparent, greatly due to the role of global regulators of transcription. This work encompasses metabolite-TF interactions, bridging the gap between the metabolic and regulatory networks, thus advancing towards an integrated network model for the understanding of cellular behavior.