An often overlooked facet of tumor biology research is the involvement of the surrounding tumor microenvironment. Increasing evidence is being presented to support a major role for stromal components in all stages of tumorigenesis including initiation, progression, and metastasis. Melanoma serves as a model for studying cellular and stromal interactions within the tumor microenvironment due to the array of cell types localized to these lesions. Here, we discuss the both the molecular mechanisms, as well as the extracellular and contextual input that contribute to melanoma progression. Special emphasis is given to the assorted cell types and their interactions with the extracellular matrix and adjacent cells. Melanoma progression also initiates development of intralesional hypoxic regions; the relative significance of hypoxia in disease is also addressed. Lastly, a number of laboratories are currently developing innovative strategies to study melanoma within a microenvironmental platform. These promising model systems and their potential for closing current gaps in knowledge of disease are reviewed. The development of such models holds translational value that cannot be achieved with most current systems. J. Cell. Biochem. 101: 862–872, 2007. © 2006 Wiley-Liss, Inc.