The rising burden of herbal and dietary supplement hepatotoxicity (HILI) is a growing concern in Western countries. The estimated incidence of HILI in well-designed prospective studies ranges from less than 1 to 3 individuals per 100,000 inhabitants/year. Herbal hepatotoxicity has a particular signature encompassing female predominance, hepatocellular type of damage with markedly elevated transaminases on presentation, more common unintentional rechallenge, and a greater risk of death/liver transplantation. Herbal hepatotoxicity recognition is particularly challenging for hepatologists because of the often hidden herbal consumption, difficulties in identifying the causative herbal component, and the possibility of contamination, adulteration, and misidentification, which preclude a proper adjudication and lead to inaccurate reporting of cases in scientific journals. Collaborative efforts to retrieve detailed phenotypic data and biological samples of patients with HILI would facilitate genomic and other molecular approaches for a better understanding of host risk factors and, hopefully, for biomarker identification.