A dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix--called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability--indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.