We herein emphasize two key aspects that should be taken into account for pharmacological intervention on melanoma: i) β3-AR plays an important role in melanoma cell aggressiveness suggesting selective β3-AR antagonists as important agents in reducing stromal fibroblasts reactivity, ii) non neoplastic stromal cells may be also targeted by this therapeutic regimen, with the interesting consequence to avoid the troublesome resistance to therapy, which is typical of cancer cells. Here, ADRB3 is linked to melanoma.