A variety of melanoma-associated antigens have been identified that mediate adhesion, growth, proteolysis, and modulation of immune response. However, the mechanisms by which human normal melanocytes become malignant are not clearly understood. Among the most consistent observations is the up-regulation of fibroblast growth factor-2 (FGF-2) and of the adhesion molecules beta3 integrin and Mel-CAM during melanoma progression. To evaluate the potential role of FGF-2, beta3 integrin and Mel-CAM in melanoma development we overexpressed FGF-2, beta3 integrin and Mel-CAM in normal human melanocytes using replication-deficient adenoviruses as a gene delivery vehicle. Fibroblast growth factor-2 overexpressing melanocytes in monolayer culture displayed cytological atypia. Furthermore, in human skin reconstructs where the physiological milieu is recreated in vitro, FGF-2-overexpressing melanocytes exhibited marked proliferation, upwards migration, cluster formation and type IV collagen expression within the epidermal compartment, simulating early radial growth phase melanoma. In contrast, overexpression of beta3 integrin and/or Mel-CAM in melanocytes did not affect their biological behaviour in human skin reconstructs. The described results of the current and previous studies emphasise the key role of FGF-2 in melanoma development and progression, underscoring the promise of FGF-2 as a target for therapy.