Caloric restriction (CR) has been extensively studied in rodents as an intervention to improve lifespan and healthspan. However, effects of CR can be strain- and species-specific. This study used publically available microarray data to analyze expression responses to CR in males from 7 mouse strains (C57BL/6J, BALB/c, C3H, 129, CBA, DBA, B6C3F1) and 4 tissues (epididymal white adipose tissue (eWAT), muscle, heart, cortex). In each tissue, the largest number of strain-specific CR responses was identified with respect to the C57BL/6 strain. In heart and cortex, CR responses in C57BL/6 mice were negatively correlated with responses in other strains. Strain-specific CR responses involved genes associated with olfactory receptors (Olfr1184, Olfr910) and insulin/IGF-1 signaling (Igf1, Irs2). In each strain, CR responses in eWAT were negatively correlated with those in human subcutaneous WAT (scWAT). In human scWAT, CR increased expression of genes associated with stem cell maintenance and vascularization. However, orthologous genes linked to these processes were down-regulated in mouse. These results identify strain-specific CR responses limiting generalization across mouse strains. Differential CR responses in mouse versus human WAT may be due to differences in the depots examined and/or the presence of “thrifty genes” in humans that resist adipose breakdown despite caloric deficit.