This review provides an overview of the assessment of the endocrine disrupting (ED) properties of carbon disulfide (CS2), following the methodology used at the European level to identify endocrine disruptors. Relevant in vitro, in vivo studies and human data are analyzed. The assessment presented here focuses on one endocrine activity, i.e., thyroid disruption, and two main adverse effects, neurotoxicity and cardiotoxicity. The data available on the different ED or non-ED modes of action (MoA), known to trigger these adverse effects, are described and the strength of evidence of the different MoA is weighted. We conclude that the adverse effects could be due to systemic toxicity rather than endocrine-mediated toxicity. This assessment illustrates the scientific and regulatory challenges in differentiating a specific endocrine disruption from an indirect endocrine effect resulting from a non-ED mediated systemic toxicity. This issue of evaluating the ED properties of highly toxic and reactive substances has been insufficiently developed by European guidance so far and needs to be further addressed. Finally, this example also raises questions about the capacity of the technics available in toxicology to address such a complex issue with certainty.