The hepatopulmonary syndrome (HPS) consists of a triad of liver dysfunction, increased alveolar-arterial oxygen gradient and intrapulmonary vascular dilations. The mechanisms of impaired arterial oxygenation are still debated but the multiple inert gases elimination technique and more recently contrast echocardiography, greatly facilitated the investigation of such mechanisms. Subsequently the cause of hypoxemia can be attributed to several mechanisms such as ventilation-perfusion mismatch, right-to-left intrapulmonary shunts and alveolar-to-capillary diffusion defect, variously implicated in the severity of the disease. SHP may result from intrapulmonary vascular dilations and angiogenesis but the pathogenesis of such abnormalities is not completely explained. The hypothesis of an imbalance in vasoactive mediators and angiogenic factors has been put forward. Increasing data support the theory that the increase in synthesis and release of nitric oxide (NO) is the key factor modulating vascular tone. If this hypothesis is true, the use of compettive inhibitors of NO synthesis should restore pulmonary vascular tone, reversing the hemodynamic changes and gas exchange impairment of HPS.