Tissue inhibitors of metalloproteinases (TIMPs) are classically known for regulating members of the metzincin protease family and are well recognized for their inhibitory effects in cancer development and progression. Despite their common evolutionary structure, the four TIMP proteins have unique properties and regulation, and produce distinct phenotypes when ablated. A comprehensive assessment of their function during tumorigenesis reveals substantial effects on cell proliferation, apoptosis, angiogenesis, invasion, and metastasis as well as a potential role in genomic instability. The TIMPs universally inhibit angiogenesis, invasion, and metastasis, but their specific effects on cell proliferation and apoptosis are both tissue specific and context dependent. They exert these effects in a metalloproteinase-dependent as well as metalloproteinase-independent manner. Knowledge gained from these biological studies provides a foundation for the full understanding of TIMP function in physiology and various pathologies as well as for the development of the next generation of therapeutic metalloproteinase inhibitors.