Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGF beta inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.