The liver is responsible for glucose synthesis in the fasting state, and glucose uptake, storage and utilization in the fed state. A phenotypic switch, normally initiated by insulin or glucagon, controls the transition between the two states, which includes transcriptional alterations that regulate metabolic enzyme abundance for multiple metabolic pathways in a coordinated manner. A network of transcription factors, coactivators, and corepressors direct these changes, thus acting as transcriptional sensors of the nutritional status of an organism. The inability of the hepatocyte to undergo this metabolic reprogramming is characteristic of diabetes mellitus. Modulations that control the amount of individual metabolic enzymes or transcription factors can initiate the fasting-to-fed transition of the hepatocyte in an insulin-independent manner. Alternatively, overexpression of key regulators of metabolism can lock hepatocytes in the fed state. These manipulations alter hepatic glucose flux leading to either amelioration or induction of diabetes mellitus. These maneuvers reveal the complexity of the coordinated mechanisms used by the liver to alter its phenotype and provide evidence for the control strength of metabolic signaling.