Human epididymis protein 4 (HE4), also called whey-acidic-protein (WAP) four-disulfide core domain protein 2 (WFDC2) is a secreted 25 kDa glycoprotein, a member of the WAP family, initially described to have tissue specific expression in the epididymis. Clinical research in the last decade revealed that HE4 is expressed in a limited number of other organs, including female reproductive tract, breast tissue, kidney, regions of the respiratory tract and nasopharynx. The gene encoding HE4, WFDC2, is composed by six exons. Five HE4 isoforms have been identified and recognized to define specific patterns differently expressed in neoplasm and normal tissues. Under physiologic conditions, HE4 is reported as protease inhibitor playing a crucial role in sperm maturation. The protein contains a WAP domain (4-disulfide core domain 2), which is known to occur in antiproteinases and proteins involved in the innate immune defense of multiple epithelia. Some studies have reported a potential role in the innate immunity of the oral cavity and respiratory tract. In pathophysiology, HE4 is likely involved in cancer progression and metastases. The protein is highly over expressed in epithelial ovarian cancer (EOC) compared to normal ovarian epithelium which is in agreement with clinical studies showing up regulation of HE4 levels in women with EOC. Since its clinical relevance has been confirmed, the HE4 is a biomarker for the detection of ovarian cancer in women with an ovarian cyst or pelvic mass as part of the Risk of Ovarian Malignancy Algorithm (ROMA) and for monitoring women diagnosed with EOC. Amongst the newly proposed biomarkers for ovarian cancer, serum human epididymis protein 4 shows the greatest potential for clinical use.