Fibrosis is a common pathology in cardiovascular disease(1). In the heart, fibrosis causes mechanical and electrical dysfunction(1,2) and in the kidney, it predicts the onset of renal failure(3). Transforming growth factor beta 1 (TGF beta 1) is the principal pro-fibrotic factor(4,5), but its inhibition is associated with side effects due to its pleiotropic roles(6,7). We hypothesized that downstream effectors of TGF beta 1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGF beta 1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.