West Nile Virus (WNV) and Usutu Virus (USUV) are neurotropic, mosquito-borne flaviviruses that primarily follow an enzootic cycle involving mosquitoes as vectors and birds as amplifying hosts. Both viruses have spread globally, with WNV first identified in Uganda in 1937 and USUV in Swaziland in 1959. WNV has caused periodic outbreaks in Europe, leading to severe neuroinvasive diseases in humans and animals, while USUV has mainly affected birds with limited human impact. Recent climate change and ecological changes have expanded their geographic range in Europe, increasing human exposure. Although they share similar biological traits, they differ in pathogenicity and impact on human and animal health. WNV is more extensively studied and a major public health concern, while USUV has gained attention due to its emergence in Europe and diverse lineages. Understanding their pathophysiology, ecology, and transmission dynamics is crucial for effective surveillance and control. WNV and USUV have become endemic in several European countries, with increasing cases in northern regions. Their co-circulation in shared host and vector populations raises important questions about transmission patterns, risk of spillover, and control strategies. Challenges include diagnostic limitations, blood safety concerns, lack of vaccines and treatments, and the need for integrated surveillance systems. Effective control requires understanding their genetic diversity, evolutionary dynamics, and ecological interactions. Current research focuses on improving diagnostic tools, monitoring viral strains, and developing vaccines and treatments. A One Health approach is essential for addressing the challenges posed by these viruses.West Nile Virus (WNV) and Usutu Virus (USUV) are neurotropic, mosquito-borne flaviviruses that primarily follow an enzootic cycle involving mosquitoes as vectors and birds as amplifying hosts. Both viruses have spread globally, with WNV first identified in Uganda in 1937 and USUV in Swaziland in 1959. WNV has caused periodic outbreaks in Europe, leading to severe neuroinvasive diseases in humans and animals, while USUV has mainly affected birds with limited human impact. Recent climate change and ecological changes have expanded their geographic range in Europe, increasing human exposure. Although they share similar biological traits, they differ in pathogenicity and impact on human and animal health. WNV is more extensively studied and a major public health concern, while USUV has gained attention due to its emergence in Europe and diverse lineages. Understanding their pathophysiology, ecology, and transmission dynamics is crucial for effective surveillance and control. WNV and USUV have become endemic in several European countries, with increasing cases in northern regions. Their co-circulation in shared host and vector populations raises important questions about transmission patterns, risk of spillover, and control strategies. Challenges include diagnostic limitations, blood safety concerns, lack of vaccines and treatments, and the need for integrated surveillance systems. Effective control requires understanding their genetic diversity, evolutionary dynamics, and ecological interactions. Current research focuses on improving diagnostic tools, monitoring viral strains, and developing vaccines and treatments. A One Health approach is essential for addressing the challenges posed by these viruses.