Among the different ancillary immunohistochemical tools that pathologists may employ in thyroid nodules, the so-called Hector Battifora’s ‘MEsothelioma’ 1 (HBME-1) staining is one of the most fascinating, since its real identity is currently unknown. In the present review, the different clinical applications of HBME-1 are analysed, with main emphasis on its role in thyroid pathology with overview on less impactful fields, such as haematopathology or mesothelial lesions. Different acceptable or good diagnostic performances were recorded for HBME-1 in thyroid pathology, being used in routine practice as one of the best tools to screen thyroid malignancy both in terms of sensitivity and specificity. From a speculative point of view, after many attempts to hunt the cryptic target antigen of this antibody, its identity still remains elusive. In this setting, the application of high-throughput technologies (mainly in situ proteomics) may be the exact route to improve the knowledge about the pathophysiology of HBME-1 and to finally unveil its true identity.