Avian influenza (AI) is a viral disease of birds that can be transmitted to other animals including humans. Outbreaks of highly pathogenic avian influenza (HPAI) subtype H5N1 occurred in poultry in Africa for the first time in 2006 following its emergence in Asia. Subsequent spread of the infection, multiple introductions, and fatal transmission to humans globally and in some African countries and connected regions underscore the importance of this transboundary animal disease to livestock, livelihoods, and public health. The prevention and control of future AI outbreaks in order to mitigate its socioeconomic and public health impact cannot be overemphasized. Repeated incursions of HPAI into Africa and intermingling of multiple susceptible hosts could drive emergence of pathogens at the interface between humans and animals in a shared environment. Intersectoral synergy for the control and mitigation of avian influenza based on the principles of One Health is therefore desirable. The need to understand the nature of the disease, its epidemiology, distribution, applied surveillance strategies, diagnosis, and measures for its control are germane and discussed in this chapter as it applies to Sahelian Africa and connected regions. Basic knowledge of influenza virus and its impact on human and animal health would help to better prepare the next generation of professionals to cope with the rapidly evolving challenges posed by this infectious disease of global reckoning.