To investigate the physiological role of menin, the protein product of the MEN1 gene, several groups have utilized gene targeting strategies to delete one or both copies of the mouse homolog Men1. Mice that are homozygous null for Men1 die during embryogenesis. Heterozygous Men1 mice are viable and develop many of the same types of tumors as humans with MEN1. In addition to conventional knockouts of Men1, tissue-specific elimination of menin using cre-lox has been achieved in pancreatic beta cells, anterior pituitary, parathyroid, liver, neural crest and bone marrow, with varying results that are dependent on cell context. In this chapter, we compare the phenotypes of the different conventional Men1 knockouts, detail the similarities and differences between Men1 pathogenesis in mice and humans and highlight results from recent crossbreeding studies between Men1 mutants and mice with null mutations in genes within the retinoblastoma pathway, including p18(Inc4c), p27(Kip1) and Rb. In addition, we discuss not only how the Men1 mutants have shed light on the role of menin in endocrine tumor suppression, but also how Men1 mutant mice have helped uncover previously unrecognized roles for menin in development, leukemogenesis and gestational diabetes.