Down syndrome (DS), trisomy chromosome 21 (Hsa21), is the most common genetic disease caused by chromosome aberration in the human genome. Modeling DS in mice has been challenging since the orthologs of Hsa21 genes map to separate segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. Although the early Ts65Dn mouse model exhibited various DS phenotypes, the duplicated fragments were randomly generated by ionizing radiation and did not include all Hsa21 orthologs. In 2004, the successful use of the Cre/LoxP recombination technique in chromosomal engineering in the construction of the Ts1Rhr mouse strain solved the problem of duplication of specific chromosome segment, resulting in the establishment of specific DS mouse models with accurate triplication of particular genes and associated phenotypes. In this review, we briefly introduce the different DS mouse models and discuss their advantages and limitations by focusing on the triplication of Hsa21 orthologs and manifestations of DS phenotypes, thereby providing some references for the selection of specific mouse models in DS research.