Mesenchymal stromal cell (MSC) therapy demands the attention of clinicians and scientists because of its potential in clinical fields that are bereft of medical options, but also because of the controversies that underlie its mode of action. MSCs are potent immune modulators, yet their biologic activity may not be innate, requiring licensing by their microenvironment. This property has prompted researchers to explore unique ways in which MSCs may be able to exert distinct biologic effects in different pathologic settings. More than 400 clinical trials have investigated the therapeutic capacity of MSCs in different pathologies, including liver disease. Along with their anti-inflammatory action, there are data to suggest that MSCs may exert direct antifibrotic effects, although enthusiasm for their use in patients has been tempered by concerns of a possible profibrotic role of endogenous MSCs in response to injury. There is a significant need for antifibrotic therapy to combat the increasing burden of patients with cirrhosis, and a concerted effort is required to determine the mechanisms by which MSCs modulate the liver's response to injury, both endogenously and after adoptive transfer. This review critically appraises the preclinical published data with regard to the capacity of MSCs to influence fibrotic response to liver injury and will explore the potential mechanisms that underpin the reported beneficial effects of MSC therapy in the context of liver injury and fibrosis.-Haldar, D., Henderson, N. C., Hirschfield, G., Newsome, P. N. Mesenchymal stromal cells and liver fibrosis: a complicated relationship.