Human epididymis protein 4 (HE4) is a 13 kDa protein coded by the gene WFDC2. Its mature glycosylated secretory form is approximately 25 kDa and consists of a single peptide and two whey acidic protein (WAP) domains containing a “four disulfide core” (FDC) encompassing eight cysteine residues. Although initially thought to have tissue-specific expression in the epididymis, HE4/WFDC2 is highly over-expressed in epithelial ovarian cancer (EOC) compared to normal ovarian epithelium. It has been recently demonstrated that over-expressed HE4/WFDC2 has a direct biological role in the promotion of OC cell proliferation, invasion and metastasis. HE4/WFDC2 levels have been monitored in EOC patients to determine recurrence or progression of the disease. HE4/WFDC2 has been used with an algorithm called Risk for Ovarian Malignancy Algorithm (ROMA) as a diagnostic tool to predict ovarian cancer. HE4 levels increase in other malignant neoplasms, especially of gynecologic (i.e., endometrial, tubal, vulvar cancer) and pulmonary origin. Accordingly, it has been proposed as a biomarker in other cancer types, in particular endometrial cancer and lung cancer. Many variables can affect the serum levels of HE4, such as age (higher in the elderly), smoking (higher by one-third in smokers than in non-smokers) and renal function.