Beta-cell-specific transgenic mice provide an invaluable model for dissecting the direct signaling mechanisms involved in regulating beta-cell structure and function. Furthermore, generating novel transgenic models is now easier and more cost-effective than ever, thanks to exciting novel approaches such as CRISPR.Here, we describe the commonly used approaches for generating and maintaining beta-cell-specific transgenic models and some of the considerations involved in their use. This includes the use of different beta-cell-specific promoters (e.g., pancreatic and duodenal homeobox factor 1 (Pdx1), rat insulin 2 promoter (RIP), and mouse insulin 1 promoter (MIP)) to drive site-specific recombinase technology. Important considerations during selection include level and uniformity of expression in the beta-cell population, ectopic transgene expression, and the use of inducible models.This chapter provides a guide to the procurement, generation, and maintenance of a beta-cell-specific transgene colony from preexisting Cre and loxP mouse strains, providing methods for crossbreeding and genotyping, as well as subsequent maintenance and, in the case of inducible models, transgenic induction.