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We observed that N-nitrosomorpholine (NMOR) given after a multi-carcinogenic treatment induces liver carcinomas with 56% lung metastasis. An additional treatment with diethylnitrosamine (DEN) with NMOR further enhanced the incidence of hepatocellular carcinoma (HCC) with lung metastasis. We have further revised the duration of NMOR treatment to establish an animal model with a simple experimental protocol and an appropriate experimental duration to facilitate investigation exploring the mechanisms of HCC metastasis and development of anti-metastatic therapeutics. We observed that DEN exposure followed by a 16-week treatment with NMOR to be a most efficient protocol for the induction of HCC metastasizing to the lung. In this review, we will discuss about the usefulness of animal models for induction of highly metastatic HCC and the assessment of the efficacy of anti-metastatic therapeutics. Additionally, we will also discuss use of these models in analysis of individual steps in the metastatic process by using non-steroidal anti-inflammatory drugs, aspirin and indomethacin, two nuclear factor kappa B (NF-κB) inhibitors, pentoxifylline and N-acetyl-L-cysteine.