2014 marked the first emergence of avian influenza A(H5N8) in Jeonbuk Province, South Korea, which then quickly spread worldwide. In the midst of the 2020-2021 H5N8 outbreak, it spread to domestic poultry and wild waterfowl shorebirds, leading to the first human infection in Astrakhan Oblast, Russia. Despite being clinically asymptomatic and without direct human-to-human transmission, the World Health Organization stressed the need for continued risk assessment given the nature of Influenza to reassort and generate novel strains. Given its promiscuity and easy cross to humans, the urgency to understand the mechanisms of possible species jumping to avert disastrous pandemics is increasing. Addressing the epidemiology of H5N8, its mechanisms of species jumping and its implications, mutational and reassortment libraries can potentially be built, allowing them to be tested on various models complemented with deep-sequencing and automation. With knowledge on mutational patterns, cellular pathways, drug resistance mechanisms and effects of host proteins, we can be better prepared against H5N8 and other influenza A viruses.