Cyclooxygenase (COX) is widely considered as the molecular target of non-steroid anti-inflammatory drugs (NSAIDs). However, due to the harmful side effect frequently observed following chronic use, the development of new anti-inflammatory agents is the matter of many studies. Signal transducers and activators of transcription (STAT) are a family of nuclear proteins mediating the action of a number of cytokines. Among them, STAT1 plays a critical role in the signal transduction pathway of interferon-gamma (IFN-gamma) and growth hormone. STAT1 cascade is one major signalling pathway converting the IFN-gamma signal into gene expression, such as inducible nitric oxide synthase (iNOS), COX, vascular cell adhesion molecules (VCAM) and intercellular cell adhesion molecules (ICAM), critically involved in different pathologies correlated to the inflammatory process. This review focuses the attention on an alternative approach to the development of novel drugs based on inhibition of STAT1 pathway. In this context, a growing interest has been focused on natural compounds. We have recently reported a several data indicating that green tea extract (GTE), St. John's Wort extract and epigallocatechin-3-gallate (EGCG) exhibit a specific and strong anti-STAT1 activity which is independent of their acclaimed strong anti-oxidant activity. More recently, GTE has been shown to protect heart damage from ischaemia/reperfusion in rats, suggesting that the protective effect of green tea might be correlated to its anti-STAT1 activity. The present review is aimed at providing data that STAT1 may potentially be claimed as a new molecular target of an anti-inflammatory treatment and that among natural compounds there are a number of anti-STAT1 substances.