To generate temporally controlled targeted somatic mutations selectively and efficiently in hepatocytes, we established SA^+/CreERT2 mice in which the tamoxifen‐dependent Cre‐ER^T2 recombinase coding sequence preceded by an internal ribosomal entry site was inserted in the 3′ untranslated region of the serum albumin (SA) gene. Whereas the wildtype SA allele was strongly expressed in the liver and at lower levels in some extrahepatic tissues, SA‐Cre‐ER^T2 fusion transcripts were only detected in the liver. The Cre‐ER^T2 protein was expressed in most if not all hepatocytes, and tamoxifen (Tam) treatments of adult mice at various ages efficiently induced Cre‐mediated recombination of LoxP flanked (floxed) alleles in these cells, but none in other cell types or tissues. Thus, SA^+/CreERT2 mice should be of great value to analyze gene function in the liver and to establish animal models of human diseases. genesis 39:167–172, 2004. © 2004 Wiley‐Liss, Inc.