Angiogenesis, the formation of blood vessels, is a major factor influencing tumor growth and metastatic capacity, and VEGF is the prototype angiogenic factor. VEGF expression is also found in the dermis and tumor stroma during the course of melanoma progression. Various oncogenes such as c-Src, v-Raf, and Ras, and multiple environmental stimuli, including hypoxia and ultraviolet radiation (UVR), can regulate VEGF expression under certain conditions. We have constructed several cell lines from a radial growth phase, primary human melanoma cell line, WM35. We have stably transfected WM35 cells with mutant activated H-ras, N-ras, dominant negative p53, or empty vector. In this report, we determined how VEGF expression and release from these melanoma cell lines were affected by the following important factors associated with melanoma initiation and progression: hypoxia, UVR, activated Ras, dominant negative p53, and culture conditions mimicking radial growth phase melanoma (monolayer culture) and vertical growth phase melanoma (spheroid culture). We found that hypoxia, but not UVR, up-regulates VEGF mRNA expression and protein release in these melanoma cells. In addition, activated Ras and dominant negative p53 enhances the hypoxia-induced VEGF protein release. We propose that hypoxia-induced VEGF release promotes tumor progression, especially in melanomas with Ras or p53 mutations.