Transcriptional regulation of animal genes has been classified into two major categories: tissue-specific and stress-inducible. Erythropoietin (EPO), an erythroid growth factor, plays a central role in the regulation of red blood cell production. In response to hypoxic and/or anemic stresses, Epo gene expression is markedly induced in kidney and liver; thus, the Epo gene has been used as a model for elucidating stress-inducible gene expression in animals. A key transcriptional regulator of the hypoxia response, hypoxia-inducible transcription factor (HIF), has been identified and cloned through studies on the Epo gene. Recently developed gene-modified mouse lines have proven to be a powerful means of exploring the regulatory mechanisms as well as the physiological significance of the tissue-specific and hypoxia-inducible expression of the Epo gene. In this chapter, several gene-modified mouse lines related to EPO and the EPO receptor are introduced, with emphasis placed on the examination of in vivo EPO activity, EPO function in nonhematopoietic tissues, EPO-producing cells in the kidney, and cis-acting regulatory elements for Epo gene expression. These in vivo studies of the Epo gene have allowed for a deeper understanding of transcriptional regulation operated in a tissue-specific and stress-inducible manner.