National Planning and coordinating Committee for the investigation of unidentified liver disease Unidentified Liver Disease (ULD) Investigational partners have been conducting a multidisciplinary investigation since 2005 to unravel the puzzle for the etiology of the ULD in some woredas of northwestern and central zones of Tigray. The investigations conducted were public health (clinical & epidemiological), livestock, Plants/weeds and environmental and anthropological studies The investigational partners concluded that all available evidence has led to the identification of an environmental hepatotoxin, pyrrolizidine alkaloid (PA), that is produced by a highly invasive local weedy plant species referred to as Ageratum conyzoides (commonly known as Hagay Fetew) as the etiologic agent of ULD. Specifically, PA toxicity in ULD patients results from ingestion of cereal grains or other agricultural products contaminated by the seeds of the PA-producing plants. Furthermore, humans also ingest the PA through consumption of certain animal products of livestock that forage on the PA containing plant. The inert PA that is ingested is then metabolized in the liver in normal enzymatic pathways creating a toxic PA metabolite that causes damage to the liver’s cells and results in the characteristic clinical presentation of case-patients. The conjecture that other infectious agents, novel pathogens, or environmental toxins (aflatoxins, algotoxins and heavy metals) may be responsible for the disease was not substantiated. The toxic effects of PA ingestion are likely compounded by dietary intake and/or deficiencies, variability in the type, quantity and duration of toxin intake as well as the individual’s physiological response, age, and gender. On the basis of all investigational findings the partners agreed that the disease should more accurately be labeled Hepatic Veno Occlusive Disease (Hepatic VOD) (International Classification for Disease (ICD-10) Code K76.5). After more than five years of research there is a need for more emphasis to be given on transitioning investigational efforts to focus on prevention activities through a holistic approach to reduce morbidity and mortality as well as environmental causes of exposure. This includes: prevention of exposure to PAs and mitigating its impact on individuals, continue the effective supportive treatment, maintain continuous surveillance that is in place to monitor disease epidemiology and impact of prevention activities and interventions as well as environmental rehabilitation. In addition to these there is also a need for communication and advocacy of the outcome of investigations through dissemination to the scientific community to share experience and the lesson learnt in the investigational and interventional collaborative efforts of the partners. This study is a typical example for “One Health” to improve the lives of all species in a sound ecosystem health through expanding the integration of interdisciplinary collaborations and communications in all aspects of healthcare for humans, animals and the environment.