Known as a uniquely regenerative tissue, the liver shows a remarkable capacity to heal without scarring after many types of acute injury. In contrast, during chronic liver disease, the liver responds with fibrosis, which can progress to cirrhosis and ultimately liver failure. The cause of this shift from a nonfibrotic to a fibrotic response is unknown. We hypothesized that stromal injury is a key event that prevents restoration of normal liver architecture. To test this, we developed a model of stromal injury using a surgical incision through the normal liver in adult and neonatal mice. This injury produces minimal cell death but locally complete stromal (extracellular matrix) disruption. The adult liver responds with inflammation and stellate cell activation, culminating in fibrosis characterized by collagen deposition. This sequence of events is remarkably similar to the fibrotic response leading to cirrhosis. Studies in neonates reveal a similar fibrotic response to a stromal injury. These findings suggest that extracellular matrix disruption leads not to regeneration but rather to scar, similar to other mammalian organs. These findings may shed light on the pathogenesis of chronic liver disease, and suggest therapeutic strategies.