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Abstract: Highly pathogenic avian influenza H5N1 has been a global concern for almost 10 years since its epidemic emergence in South-east Asia in 2003/2004. Despite large investment of resources into the region, the infection has not been eradicated and continues to result in outbreaks in poultry and a small number of human fatalities. This review synthesizes the knowledge base generated by a vast number of research activities conducted in the region and beyond, and adopts an interdisciplinary perspective consistent with the one health paradigm towards analysing the problem and formulating possible policy solutions. A key outcome of the work has been the need to integrate socio-economic and anthropological dimensions with any disease control and prevention activities traditionally informed by primarily epidemiological, virological and pathological attributes of the infection in poultry and wild waterbirds. Recommendations at a broad conceptual level are presented that acknowledge the diversity in the region with respect to livestock production, as well as the changing nature of the risk landscape as a consequence of the rapid economic development which some of the countries in the Greater Mekong sub-region are currently undergoing, as well as their strong trade links with China as the major economic power in East Asia. [Copyright &y& Elsevier]