SUMMARY The aim of the present review is to discuss: (i) the role of tissue factor (TF) in the heart and focus on its potential role in maintaining normal extracellular cardiac homeostasis; (ii) the means by which TF may be contributing to extracellular matrix regulation and vascular maintenance; and (iii) potential mechanisms whereby reduced TF expression leads to cardiac fibrosis. Tissue factor is the main initiator of the coagulation cascade in response to tissue injury, but it is also involved in numerous other biological processes, including angiogenesis, cell migration, apoptosis, metastasis and inflammation. Tissue factor is implicated in cardiovascular disease and its localization and level of expression in cardiomyocytes suggests a unique role in maintaining the structure and function of cardiac muscle. It has been shown that TF−/– mice die in utero as a result of disrupted yolk sac vasculature. Low‐TF mice, which have transgenic expression of TF at less than 1% of normal levels, are rescued from lethality. Low‐TF mice develop cardiac fibrosis in a gender‐dependent manner that may be dependent on differential expression of urokinase plasminogen activator. Intracardiac bleeding in low‐TF mice may occur as a result of a primary haemostasis defect and/or as a result of disrupted vascular maintenance. The mechanism, when elucidated, will have important therapeutic implications and may provide novel strategies for the treatment of cardiac fibrosis.