Fibroblasts are a special type of interstitial cell that has an essential role in maintaining the structural framework of tissues and organs. In response to injury, fibroblasts are activated and produce large amounts of extracellular matrix proteins. Fibroblast activation has a crucial role in tissue repair and wound healing. However, uncontrolled and persistent activation of fibroblasts ultimately leads to fibrotic diseases of organs such as the kidney, liver, lung and heart. Activated fibroblasts predominantly originate from the local activation and expansion of resident fibroblasts and pericytes. A diverse array of extracellular cues, including soluble factors, extracellular vesicles, matricellular proteins and mechanical stiffness, induce fibroblast activation after tissue injury. Fibroblast activation primarily takes place in the fibrogenic niche, a unique tissue microenvironment in which fibroblasts interact with injured parenchymal cells, inflammatory cells and endothelial cells. The fates of activated fibroblasts, including apoptosis, senescence, dedifferentiation and lineage reprogramming, determine the outcome of tissue repair and organ fibrosis. Potential therapeutic strategies for fibrotic diseases include disrupting the formation of the fibrogenic niche, inhibiting fibroblast activation, promoting fibroblast depletion, accelerating fibrosis resolution or promoting tissue repair and regeneration.