‘Jack of all trades, master of everything’ is a fair label for transforming growth factor β1 (TGF-β) – a cytokine that controls our life at many levels. In the adult organism, TGF-β1 is critical for the development and maturation of immune cells, maintains immune tolerance and homeostasis, and regulates various aspects of immune responses. Following acute tissue damages, TGF-β1 becomes a master regulator of the healing process with impacts on about every cell type involved. Divergence from the tight control of TGF-β1 actions, for instance caused by chronic injury, severe trauma, or infection can tip the balance from regulated physiological to excessive pathological repair. This condition of fibrosis is characterized by accumulation and stiffening of collagenous scar tissue which impairs organ functions to the point of failure. Fibrosis and dysregulated immune responses are also a feature of cancer, in which tumor cells escape immune control partly by manipulating TGF-β1 regulation and where immune cells are excluded from the tumor by fibrotic matrix created during the stroma ‘healing’ response. Despite the obvious potential of TGF-β-signalling therapies, globally targeting TGF-β1 receptor, downstream pathways, or the active growth factor have proven to be extremely difficult if not impossible in systemic treatment regimes. However, TGF-β1 binding to cell receptors requires prior activation from latent complexes that are extracellularly presented on the surface of immune cells or within the extracellular matrix. These different locations have led to some divergence in the field which is often either seen from the perspective of an immunologists or a fibrosis/matrix researcher. Despite these human boundaries, there is considerable overlap between immune and tissue repair cells with respect to latent TGF-β1 presentation and activation. Moreover, the mechanisms and proteins employed by different cells and spatiotemporal control of latent TGF-β1 activation provide specificity that is amenable to drug development. This review aims at synthesizing the knowledge on TGF-β1 extracellular activation in the immune system and in fibrosis to further stimulate cross talk between the two research communities in solving the TGF-β conundrum.