High-pathogenicity avian influenza (HPAI) viruses have arisen from low-pathogenicity avian influenza (LPAI) viruses via changes in the hemagglutinin proteolytic cleavage site, which include mutation of multiple nonbasic to basic amino acids, duplication of basic amino acids, or recombination with insertion of cellular or viral amino acids. Between 1959 and 2019, a total of 42 natural, independent H5 (n = 15) and H7 (n = 27) LPAI to HPAI virus conversion events have occurred in Europe (n = 16), North America (n = 9), Oceania (n = 7), Asia (n = 5), Africa (n = 4), and South America (n = 1). Thirty-eight of these HPAI outbreaks were limited in the number of poultry premises affected and were eradicated. However, poultry outbreaks caused by A/goose/Guangdong/1/1996 (H5Nx), Mexican H7N3, and Chinese H7N9 HPAI lineages have continued. Active surveillance and molecular detection and characterization efforts will provide the best opportunity for early detection and eradication from domestic birds.