Altered interactions between the extracellular matrix and cells play an important part in tumorigenesis and metastasis. As a member of a matricellular glycoprotein, fibulin-5 is expressed in elastin-rich tissues and organizes the matrix structures by interacting with many extracellular proteins. Fibulin-5 expression is closely associated with normal embryonic development and organogenesis. Mice deficient for the fibulin-5 gene exhibit systemic elastic fiber defects with manifestation of loose skin, emphysematous lungs and tortuous vessels. Additionally, fibulin-5 null mice exhibited increased angiogenesis after wound healing or PVA sponge implantation and matrigel implantation experiments show that fibulin-5 inhibits vessel formation, suggesting its function as an angiogenesis inhibitor. Fibulin-5 also plays critical roles in proliferation, migration and invasion of certain tumors, and the effect of fibulin-5 on tumorigenesis appears to be largely context-dependent. This effect might involve the inhibiting action of fibulin-5 on angiogenesis. This review focuses on recent advances in our understanding of the roles of fibulin-5 in tumorigenesis: both tumor promoting and suppressing activities of fibulin-5 are reviewed, and the emerging evidence of its promising potential for therapeutic options and/or targets in the treatment of cancer is also highlighted.