Maintenance of body water homeostasis is a fundamental homeostatic mechanism in mammals. Understanding the basic mechanisms of how water balance is maintained, or dysfunctional in certain diseases is thus of clinical importance. In recent years, application of transgenic and knockout mouse technology is providing critical new information about urinary concentrating processes and thus mechanisms for maintaining body water homeostasis. In this chapter we provide a brief overview of genetic mouse model generation, and then summarize findings in transgenic and knockout mice pertinent to our understanding of the urinary concentrating mechanism, focusing predominantly on mice in which expression of specific renal transporters or receptors has been deleted.