The zebrafish model system is one of the most widely used animal models for developmental research and it is now becoming an attractive model for drug discovery and toxicological screening. The completion of sequencing the zebrafish genome and the availability of full-length cDNAs and DNA microarrays for expression analysis, in addition to techniques for generating transgenic lines and targeted mutations, have made the zebrafish model even more attractive to researchers. Recent data indicate that the regulation of glucose metabolism in zebrafish, through the production of insulin, is similar to mammalian models, and many of the genes involved in regulating blood glucose levels have been identified in zebrafish. The data presented here show that adult zebrafish respond to anti-diabetic drugs similarly to mammalian models, by reducing blood glucose levels. Furthermore, we show that the expression of phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes a rate-limiting step in gluconeogenesis and is transcriptionally regulated by glucagon and insulin, is regulated in larval zebrafish similarly to that seen in mammalian systems, and changes in PEPCK expression can be obtained through real-time PCR analysis of whole larval RNA. Taken together, these data suggest that larval zebrafish may be an appropriate model for the examination of glucose metabolism, using PEPCK as an indicator of blood glucose levels.