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Knockout of C/EBP␣ causes a severe loss of liver function and, subsequently, neonatal lethality in mice. By using a gene replacement approach, we generated a new C/EBP␣-null mouse strain in which C/EBP␤, in addition to its own expression, substituted for C/EBP␣ expression in tissues. The homozygous mutant mice C/ebp␣ ␤/␤ are viable and fertile and show none of the overt liver abnormalities found in the previous C/EBP␣-null mouse line. Levels of hepatic PEPCK mRNA are not different between C/ebp␣ ␤/␤ and wild-type mice. However, despite their normal growth rate, C/ebp␣ ␤/␤ mice have markedly reduced fat storage in their white adipose tissue (WAT). Expression of two adipocyte-specific factors, adipsin and leptin, is significantly reduced in the WAT of C/ebp␣ ␤/␤ mice. In addition, expression of the non-adipocyte-specific genes for transferrin and cysteine dioxygenase is reduced in WAT but not in liver. Our study demonstrates that when expressed from the C/ebp␣ gene locus, C/EBP␤ can act for C/EBP␣ to maintain liver functions during development. Moreover, our studies with the C/ebp␣ ␤/␤ mice provide new insights into the nonredundant functions of C/EBP␣ and C/EBP␤ on gene regulation in WAT.