Melanoma is one of the most aggressive and less chemotherapy-responsive human cancers, representing a major public health issue worldwide. The early diagnosis still represents the best approach in order to reduce mortality, especially in advanced stages. Preclinical evidence, collected through several in vitro and in vivo models, has been accumulating about the pathophysiological involvement of β-adrenoceptors in melanoma progression. This involvement has been paralleled by the evidence that drugs blocking β-adrenoceptors (β-blockers) may have a relevant role in the treatment of melanoma and in the prevention of its progression. β-blockers are a class of drugs extensively used in clinical practice, not limited to cardiovascular therapeutics. Evidence collected through retrospective and prospective observational studies suggests that treatment with β-blockers, mainly propranolol, is able to delay melanoma progression. Although conclusive evidence is still lacking, current knowledge proposes β-blockers as an opportunity for antitumor treatment in melanoma. Clinical trials are needed in order to prove their claimed efficacy. Graphical Abstract.