Neuronal PAS domain protein 2 (Npas2) is a clock gene expressed widely in brain and peripheral tissues. NPAS2 is responsive to cellular metabolic state and mutation of this gene impairs adaptation to restricted feeding schedules, suggesting that NPAS2 is required for effective control of a food-entrainable oscillator. However, an alternative possibility, that NPAS2 is required for detection of metabolic cues signaling energy deficiency or for arousal of appropriate behavioral responses to such cues, as not been directly examined. Therefore, we examined the effect of targeted disruption of Npas2 on responses to several acute and chronic metabolic challenges. We found that under normal light–dark and ad libitum feeding conditions, Npas2 knockout (KO) mice did not differ from wild-type (WT) controls with respect to diurnal feeding or blood glucose levels, body weight or size or body composition. Furthermore, feeding responses to overnight food deprivation, insulin- or 2-deoxy-d-glucose (2DG)-induced glucoprivation, mercaptoacetate (MA)-induced blockade of fatty acid oxidation and cold exposure did not differ by genotype. However, KO mice lost more weight than WT during overnight food deprivation and when placed on a 4-h restricted feeding schedule, even though food intake did not differ between groups. Thus, it appears that NPAS2 is not required for detection of or behavioral responses to a variety of acute or chronic metabolic deficits, but is more likely to be involved in effective synchronization of feeding behavior with scheduled food availability.