Although lactation is the only physiological function of the mammary gland, little is known about the molecular events required for secretory activation and milk production. Genetically altered mice have been used extensively to study mammary gland development during puberty and pregnancy, as well as mammary tumorigenesis. A number of approaches have been used to produce genetic modifications in mammary glands of mice, including transgenic mice utilizing mammary specific promoters, traditional knockout mice, mammary-specific gene deletion, and conditionally-regulated transgenes. The same technologies can be used to study secretory activation and lactation; however only a comparatively small number of studies to date have used these approaches to study these events. In this paper we review the technologies available to make genetically modified mice for the study of secretory activation and lactation as well as specific analytical procedures that can be used to characterize mice with lactation defects.