During embryogenesis, the primordial microcirculation is formed through a process known as vasculogenesis. The term “vasculogenic mimicry” has been used to describe the manner in which highly aggressive, but not poorly aggressive melanoma tumor cells express endothelial and epithelial markers and form vasculogenic-like networks similar to embryonic vasculogenesis. Vasculogenic mimicry is one example of the remarkable plasticity demonstrated by aggressive melanoma cells and suggests that these cells have acquired an embryonic-like phenotype. Since the initial discovery of tumor cell vasculogenic mimicry by our laboratory, we have been focusing on understanding the molecular mechanisms that regulate this process. This review will highlight recent findings identifying key signal transduction events that regulate melanoma vasculogenic mimicry and their similarity to the signal transduction events responsible for promoting embryonic vasculogenesis and angiogenesis. Specifically, this review will focus on the role of the Eph receptors and ligands in embryonic vasculogenesis, angiogenesis, and vasculogenic mimicry. Developmental Dynamics 236:3283–3296, 2007. © 2007 Wiley-Liss, Inc.