Abstract: Mucosal melanoma is a rare melanoma subtype with distinct biological, clinical, and management considerations. Its characteristically low mutational burden, high copy number and structural variants, and prevalence of unique driver mutation are important for understanding the natural history of mucosal melanoma and its response to various treatments. Knowledge regarding optimal treatment strategies for mucosal melanoma is limited. Thus, clinical trials, particularly those using a combination of newer targeted therapies and immunotherapies, are investigating novel treatment approaches. The expression of vascular endothelial growth factor (VEGF) is considered to be associated with poor outcomes in patients with mucosal melanoma, blocking VEGF signaling may control the growth of melanoma lesions. Besides its role in vascular growth, VEGF has emerged as an important immunosuppressive agent in the tumor microenvironment. In vivo studies have shown that angiogenesis inhibition, specifically the simultaneous inhibition of the VEGF receptor and PD-1 pathways, synergistically increased T-cell infiltration and suppressed tumor growth. The treatment combination of PD-1 blockade and a small-molecule VEGF receptor inhibitor for patients with previously untreated advanced mucosal melanoma demonstrated a manageable safety profile and durable antitumor activity. Overall, despite considerable therapeutic advances in the treatment of melanoma, the poor prognosis of patients with mucosal melanoma mandates continued emphasis on laboratory and clinical research for this rare melanoma subtype.