Melanoma is one of the most serious forms of skin cancer with the highest mortality rate among all the skin cancers diagnosed in the United States. It is a cancer of the melanocytes mainly targeting the dermis, however occasionally it also initiates in uveal, acral, and mucosal regions. The studies show that this disease affects mostly the white population. Advanced stage melanomas are presently treated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors and immunotherapies. These treatments are moderately successful since patients develop resistance or respond weakly to the therapy leading to recurrence. For better understanding of the tumor biology and to design novel therapeutic targets, humanized in vivo murine models from patient-derived xenografts (PDX) are developed. A lot of success to available treatments and knowledge of genes involved in melanoma initiation and progression can be attributed to various preclinical mouse models developed in the last decade. In this chapter, we discuss these models and some recent advancement in the preclinical animal models such as PDX models. © 2019 Elsevier Inc. All rights reserved..