Transforming growth factor-beta (TGF-beta) is a potent modulator of immune and neural cell function and plays an important role in neuro-immune interaction. TGF-beta is therefore considered an attractive therapeutic target in brain injury and neurodegeneration. However, the role of TGF-beta in disease is highly cell type- and context-dependent. Depending upon context, the activation of this signaling cascade has either beneficial or deleterious consequences. We have extensive experience in modulating TGF-beta signaling in a controlled manner to dissect the role of TGF-beta in disease and to harness the therapeutic potential of TGF-beta signaling modulation.