Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints normally placed upon their growth and survival. During cancer progression, indolent tumors experience an array of genetic and epigenetic events that ultimately coordinate the development of tumor metastasis, which is the most lethal facet of cancer and the leading cause of cancer-related death. The therapeutic necessity to combat tumor metastasis continues to drive investigations aimed at identifying novel regulators of this deadly process. Fibulin-5 is a newly described extracellular matrix protein that is important for normal embryonic development and organogenesis. Fibulin-5 expression may also be associated with the suppression of tumor formation through its control of cell proliferation, motility and angiogenic sprouting. Here, the tumor suppressing activities of fibulin-5 are reviewed, and the potential use and targeting of fibulin-5 to combat growth and metastasis of human malignancies is discussed.