The liver is a major site for carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). In the last decade, increasing evidence has emerged to show that nutrients, in particular, glucose and fatty acids, are able to regulate hepatic gene expression in a transcriptional manner. Indeed, although insulin was long thought to be the major regulator of hepatic gene expression, it is now clear that glucose metabolism rather that glucose itself also contributes substantially to the coordinated regulation of carbohydrate and lipid homeostasis in liver. In fact, the recent discovery of the glucose-signaling transcription factor carbohydrate responsive element binding protein (ChREBP) shed some light on the molecular mechanisms by which glycolytic and lipogenic genes are reciprocally regulated by glucose and fatty acids in liver. Here, we will review some of the recent studies that have begun to elucidate the regulation and function of this key transcription factor in liver. Indeed, a better understanding of the mechanisms by which glucose and fatty acids control hepatic gene expression may provide novel insight into the development of new therapeutic strategies for a better management of diseases involving blood glucose and/or disorders of lipid metabolism.