The present study performed a combination of In vitro and In vivo tests, examining the role of the AM system on the growth of melanoma cell lines and xenografts, respectively. Even though targeted medicines and immunotherapies have made tremendous progress, metastatic melanoma is an aggressive disease that can provide a serious therapeutic challenge. This underscores the necessity for the identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is expressed significantly in many tumor types. By binding to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3), AM affects angiogenesis and tumor progression. In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrated an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (aAM) and anti-AMR antibodies (AMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with AMR, thus indicating that melanoma cells are regulated by AM. Reduced numbers of vessel structures showed that systemic administration of AMR decreased the neovascularization of in vivo Matrigel plugs containing melanoma cells. This suggests that AM is one of the factors derived from melanoma cells that is responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. Tumor regression was achieved in vivo by AMR treatment, which inhibited angiogenesis and lymphangiogenesis and reduced proliferation in MeWo xenografts. Upon histological evaluation, tumors treated with AMR exhibited indications of disrupted tumor vascularity, including a notable reduction in lymphatic endothelial cells and a depletion of vascular endothelial cells. Finally, the representation of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.