Avian influenza virus (AIV) poses a significant challenge to poultry production, with negative repercussions for both the economy and public health worldwide. Since January 2003, a total of 868 human cases of AIV H5N1 have been reported from four countries in the Western Pacific Region, as of 9 March 2023. When AIVs are circulating in poultry, there is a risk of sporadic infections and small clusters of human cases due to exposure to infected poultry or contaminated environments. The increase in reported A(H5N1) infections may reflect continued virus circulation in birds, as well as enhanced surveillance and diagnostic capacity resulting from the response to the COVID-19 pandemic. Numerous countermeasures, including vaccines and antiviral treatments, are available for influenza infection. However, their effectiveness is often debated due to the ongoing resistance to antivirals and the relatively low and unpredictable efficiency of influenza vaccines compared to other vaccines. Vaccination remains the primary method for preventing influenza acquisition or avoiding serious complications related to the disease. In this review, we summarize the global landscape of the Influenza A virus and provide insights into human clinical symptomatology. We call for urgent investment in genomic surveillance strategies to timely detect and shape the emergence of any potential viral pathogen, which is essential for epidemic/pandemic preparedness.