The invention provides novel methods and compositions for modulating gluconeogenesis through modulation of PGC-1 activity or expression. Also provided are methods for identifying compounds that modulate gluconeogenesis through modulation of PGC-1 activity or expression, as well as methods for identifying compounds that modulate the interaction of PGC-1 with PGC-1 target molecules. Further provided are methods for treating disorders characterized by aberrant gluconeogenesis.