The cytokine transforming growth factor-beta (TGF-β) has multiple effects in both physiological and pathological conditions. TGF-β is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-β in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-β yield elevated, rather than decreased, TGF-β levels, posing a 'TGF-β paradox.' In this review, we discuss recent findings concerning the relationship of TGF-β, ECM molecules, and latent TGF-β activation and propose a model to resolve the 'TGF-β paradox.'