The extracellular matrix proteases act in diverse physiological and pathological processes involving tumor growth, angiogenesis, and pregnancy through the cleavage of extracellular matrix (ECM) and non-matrix proteinaceous substrates. Matrix metalloproteinases (MMPs) constitute a main family among the ECM proteases. Endogenous tissue inhibitors of metalloproteinases (TIMPs), as one kind of MMPs inhibitors (MMPIs), reduce the excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in cancer tumorigenesis, angiogenesis, as well as embryo implantation and trophoblastic invasion during pregnancy. A variety of literature concerns the correlated changes in MMPs and MMPIs during the formation of cancer and pregnancy-related complications. Importantly, MMPs and TIMPs may act as regulators of signaling pathways through the cleavage of non-matrix substrates, including cytokines, chemokines, and growth factors. In this review, we concentrate on mutual interactions between ECM proteases and cytokines during cancer development and pregnancy. The current knowledge in the field of identified ECM proteases will be contributive to the innovative therapeutic intervention in both cancer and pregnancy-related processes.