With around 200 million people affected worldwide, the incidence of type II diabetes has reached pandemic dimensions. As a hallmark of the type II diabetic phenotype, peripheral insulin resistance promotes chronic hyperglycemia, which represents a major cause of vascular complications and relies substantially on unrestricted de novo glucose synthesis (gluconeogenesis) in the liver of these patients. In this metabolic setting, a concomitant predominance of counterregulatory hormones—in particular, pancreatic glucagon acting via the intracellular cAMP pathway—further aggravates hepatic glucose production (Saltiel, 2001). Deciphering how counterregulatory hormones regulate hepatic glucose output represents a major challenge for the identification of potential new therapeutic targets. Recent work by Pei and colleagues (2006b) advances our understanding of gluconeogenic control by investigating the role of NR4A orphan nuclear receptors in liver metabolism.