Biomarkers have a wide range of applications in the management of several cancers. To date serum markers have been the most extensively used biomarkers in everyday practice but few markers are elevated in preclinical or premalignant disease, limiting their importance for estimating risk or for screening. Human epididymis protein-4 (HE4) is a novel serum marker which is more sensitive in the prediction of risk of ovarian malignancy than CA125 alone in patients with a pelvic mass. HE4 in combination with CA125 appears to be an effective tool for the early detection of recurrence or monitoring the response to therapy. Risk of Ovarian Malignancy Algorithm, utilizing the dual marker combination of HE4 and CA125, can be used to stratify both postmenopausal and premenopausal women into high- and low-risk groups, allowing for an effective triage of women to appropriate institutions for their care. A review of HE4 and its feasibility as a novel diagnostic tool in the management of epithelial ovarian cancer is presented.