Kawasaki disease (KD) is a systemic vasculitis affecting young children, often leading to coronary artery aneurysms. Its etiology remains unknown, but recent epidemiological data from Japan, the country with the highest incidence, suggest potential infectious triggers, including person-to-person transmission. However, the rising incidence in Japan indicates increasing exposure that cannot be fully explained by such transmission. The disease's etiology is critical for developing accurate diagnostic tests and effective treatments. KD diagnosis relies on clinical criteria due to the lack of a specific test, leading to potential under- or overdiagnosis. Intravenous immunoglobulin (IVIG) is effective in reducing aneurysm prevalence but is expensive and not accessible globally. Coronary artery damage from vasculitis can lead to thrombosis and long-term cardiovascular complications. Historical records suggest KD was new in Asia post-WWII and existed in the West since the 19th century. The disease's etiology is still debated, with hypotheses ranging from infectious agents to genetic factors. Epidemiological data from Japan show three major epidemics, suggesting a novel agent's introduction into a susceptible population. The annual rise in cases in older children suggests increasing exposure to an airborne trigger. Wind-borne transmission is a hypothesis, supported by the geographic coherence of KD cases in Japan. Person-to-person transmission is also suggested by studies showing a risk factor for having an older sibling. The COVID-19 pandemic reduced KD cases, indicating possible respiratory transmission. However, the persistent increase in cases suggests ongoing exposure. The disease's etiology is also linked to environmental factors, including oxidative stress and microbiome changes. Animal models and genetic studies suggest a complex genetic pattern influencing susceptibility. Research into immune responses, biomarkers, and genetic factors is ongoing. The etiology of KD remains unresolved, with potential implications for other inflammatory diseases. Future research should focus on environmental and genetic factors, leveraging big data and molecular tools to identify the disease's cause. Understanding KD's etiology is crucial for improving diagnosis, treatment, and preventing long-term complications.Kawasaki disease (KD) is a systemic vasculitis affecting young children, often leading to coronary artery aneurysms. Its etiology remains unknown, but recent epidemiological data from Japan, the country with the highest incidence, suggest potential infectious triggers, including person-to-person transmission. However, the rising incidence in Japan indicates increasing exposure that cannot be fully explained by such transmission. The disease's etiology is critical for developing accurate diagnostic tests and effective treatments. KD diagnosis relies on clinical criteria due to the lack of a specific test, leading to potential under- or overdiagnosis. Intravenous immunoglobulin (IVIG) is effective in reducing aneurysm prevalence but is expensive and not accessible globally. Coronary artery damage from vasculitis can lead to thrombosis and long-term cardiovascular complications. Historical records suggest KD was new in Asia post-WWII and existed in the West since the 19th century. The disease's etiology is still debated, with hypotheses ranging from infectious agents to genetic factors. Epidemiological data from Japan show three major epidemics, suggesting a novel agent's introduction into a susceptible population. The annual rise in cases in older children suggests increasing exposure to an airborne trigger. Wind-borne transmission is a hypothesis, supported by the geographic coherence of KD cases in Japan. Person-to-person transmission is also suggested by studies showing a risk factor for having an older sibling. The COVID-19 pandemic reduced KD cases, indicating possible respiratory transmission. However, the persistent increase in cases suggests ongoing exposure. The disease's etiology is also linked to environmental factors, including oxidative stress and microbiome changes. Animal models and genetic studies suggest a complex genetic pattern influencing susceptibility. Research into immune responses, biomarkers, and genetic factors is ongoing. The etiology of KD remains unresolved, with potential implications for other inflammatory diseases. Future research should focus on environmental and genetic factors, leveraging big data and molecular tools to identify the disease's cause. Understanding KD's etiology is crucial for improving diagnosis, treatment, and preventing long-term complications.