High forkhead box protein 01 (Foxo1) activity in liver increases gluconeogenesis and hepatic glucose output; thus, Foxo1 is accused of contributing to the pathology of diabetes (for review, see Ref. 1). Until recently, other closely related members of the forkhead/wingedhelix family of transcriptional regulators, Foxo3 and Foxo4, have received little attention because of negligible knockout phenotypes in mice (2, 3). In the current issue of Endocrinology, Zhang et al. (4) reveal new metabolic functions for these seemingly redundant family members through analysis of overlapping, liver-specific deletions of the three Foxo proteins. This elegant new study illustrates the increasing complexity of the transcriptional networks controlling metabolism and emphasizes the importance of considering these interactions when devising new therapeutic strategies. The Fox transcriptional regulators (including Foxa, Foxo, Foxm, and Foxl proteins) have well-known roles in liver organogenesis (for review, see Ref. 5). However, in terms of liver metabolism, Foxo1 has gained the most notoriety due to its potent regulation of glucose homeostasis. Since the discovery of Foxo1 as a key regulator of gluconeogenic gene expression, there has been great interest in developing therapies to block hepatic Foxo1 activity in diabetic patients to reduce glycemia. Toward this end, Zhang et al. (4) show that a liver-specific knockout of Foxo1 can reduce blood glucose levels, and that concurrent reduction of Foxo3 further improves glycemia and whole-body insulin sensitivity. These particular data are not surprising, as another recent study reports similar findings (6). Although they differ in their conclusions concerning the role of Foxo4 in glycemia, these papers and others provide strong evidence that reducing Foxo activity in liver may indeed be useful to treat diabetes and metabolic syndrome. However, pertinent information contradicting this dogma is later revealed as Zhang et al. (4) further characterize the knockout metabolic phenotypes. Zhang et al. observe that loss of both Foxo1 and Foxo3 also results in significant hypertriglyceridemia and hypercholesterolemia due to increased hepatic lipid secretion and mild steatosis. These new data not only reveal previously unrecognized metabolic functions for the mostly ignored Foxo3 but also demonstrate that Foxo-regulated metabolic networks may be far more complex than originally thought. By dissecting both global and target gene expression, Zhang et al. (4) suggest that Foxo1 and Foxo3 synergistically suppress key lipogenic pathways, in addition to enhancing genes controlling glucose metabolism. This has significant therapeutic relevance, as it implies that targeting Foxo proteins for the treatment of hyperglycemia may also have unforeseen negative consequences on cardiovascular health. The metabolic outcome of reducing Foxo expression in diabetic models has been of great interest for a number of years (see Table 1 for summary). Thus, evidence of hyperlipidemia in mice on a Foxo-null background can be found in other reports. An independent triple Foxo1/3/4 hepatic Foxo-null mouse line also displays hypertriglyceridemia and increased lipogenesis, but only after exposure to a high-fat diet (7). Unfortunately, this earlier study presents data only for the triple knockout and does not address the relative contributions of individual Foxo proteins. In contrast, Zhang et al. (4) systematically analyze the detailed phenotype of singleand double-knockout mice, shedding light on the role of each family member in liver metabolism. Interestingly, the new study does not include detailed phenotypic or expression data for the triple knockout, with the authors citing lack of an additive effect. These