Malignant melanoma arises from a genetic defect in pigment producing cells known as melanocytes. Melanoma is not the most common type of skin cancer; however, it is the deadliest type. The ability of malignant melanoma cells to metastasize poses a great health risk. Previous studies have shown that highly aggressive human melanoma cells (most likely to metastasize) unlike poorly aggressive melanoma cells (least likely to metastasize), express markers associated with endothelial and epithelial cells and form vascular-like networks, in a process called vasculogenic mimicry (VM). The objective of this study was to determine the expression levels of the tyrosine kinase receptor EphB4 and its ligand ephrin-B2 in highly aggressive human melanoma cells compared to poorly aggressive human melanoma cells. PCR primers targeting the EphB4 and ephrin-B2 gene were designed and PCR was performed. Our results indicate that EphB4 is expressed by both highly and poorly aggressive human melanoma cells whereas ephrin-B2 displays an increased level of expression in highly aggressive human melanoma cells. Future research aims are to understand the functional significance of this receptor/ligand pair and its role in mediating melanoma vasculogenic mimicry.