Stat5a is essential for the development of the adult mammary gland and lactogenesis. Prolactin (PRL) induces mammary gland development and lactogenesis by activating STAT proteins, particularly Stat5a and Stat5b. In this study, the authors disrupted the Stat5a gene in mice using gene targeting. Despite normal development and fertility, Stat5a-deficient mice showed impaired lobuloalveolar outgrowth during pregnancy and failed to lactate after parturition due to a lack of terminal differentiation. Although Stat5b, which shares 96% sequence similarity with Stat5a, was present in these mice, it could not compensate for the absence of Stat5a. These findings demonstrate that Stat5a is the primary and necessary mediator of mammopoietic and lactogenic signaling.Stat5a is essential for the development of the adult mammary gland and lactogenesis. Prolactin (PRL) induces mammary gland development and lactogenesis by activating STAT proteins, particularly Stat5a and Stat5b. In this study, the authors disrupted the Stat5a gene in mice using gene targeting. Despite normal development and fertility, Stat5a-deficient mice showed impaired lobuloalveolar outgrowth during pregnancy and failed to lactate after parturition due to a lack of terminal differentiation. Although Stat5b, which shares 96% sequence similarity with Stat5a, was present in these mice, it could not compensate for the absence of Stat5a. These findings demonstrate that Stat5a is the primary and necessary mediator of mammopoietic and lactogenic signaling.