Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs) and the balance between MMPs/TIMPs regulates the extracellular matrix (ECM) turnover and remodeling during normal development and pathogenesis. Increasing evidence indicates a much more complex role for TIMPs during tumor progression and angiogenesis, in addition to their regulation of MMP-mediated ECM degradation. In this article, we review both the MMP-dependent and -independent actions of TIMPs for the regulation of cell death, cell proliferation, and angiogenesis, with a particular emphasis on TIMP-1 in the regulation of tetraspanin/integrin-mediated cell survival signal transduction pathways.