NO has broad and sometimes dichotomous roles in cancer. The effects of NO in tumours depend on the type and localization of NOS isoforms, concentration and duration of NO exposure, and cellular sensitivity to NO. Hepatocellular carcinoma (HCC) is a common and lethal disease for which no effective therapy other than sur4gical resection exists. Over two decades of research has yielded evidence that NO generated by the inducible NOS (iNOS or NOS2) contributes to HCC progression in at least a subset of patients with HCC. The co-expression of iNOS with COX-2 may portend a particularly aggressive cancer phenotype in HCC and at the same time reveal an opportunity for pharmacological intervention. In this review, we focus on what is known about the influence of NO in HCC neoplastic transformation, proliferation and apoptosis, angiogenesis, invasion, and metastasis, cancer stem cells, and the host immune response against the tumour. We discuss the implications of recent findings for targeting the NO pathways in HCC.