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Avian influenza virus (AIV) can cause a variety of diseases in domesticated poultry ranging from asymptomatic to severe systemic infections with 100% morbidity and mortality. Some strains of AIV have frequently crossed the species barrier between birds and mammals including human posing a serious threat to public health. Therefore, control of AIV infections in poultry considered the first line of defense to prevent or reduce the incidence of AIV in humans. For many years, biosecurity, surveillance and stamping out of infected poultry flocks were the primarily control strategy to eliminate infection in poultry. Since the last decade, vaccination against the disease has been implemented in a number of countries to limit the socioeconomic impact of the disease and reduce the costs of test-and-slaughter. Nevertheless, the infection has been established in several developing countries with under-resourced poultry industry infra-structure and the virus evolved into resistant variants. Non-classical strategies as integrated and/or complementary approaches to reduce the current burden of AIV epidemics in poultry, including the H5N1 subtypes, merit further in-depth research and evaluation. In this chapter, we reviewed in details the in-vivo and in-vitro effect of chemotherapeutics, natural antivirals and probiotics on AIV. Moreover, approaches for the control of the disease in poultry using advanced molecular techniques including RNA interference, cytokines, host genetic selection and development of transgenic chickens were also summarized.