INTRODUCTION: There is a need to improve the diagnosis and prognosis of ovarian carcinoma, particularly the serous type of cancer. Mesothelin and HE4 are two novel biomarkers which are expressed in serous ovarian carcinoma and can be measured in serum and other body fluids, including urine, by using ELISA. The measurement of antibodies to these markers can provide additional useful information. AREAS COVERED: A literature search was performed to as recent as December 1 2010, using the Internet (e.g. PubMed) on articles concerning mesothelin and HE4 for the diagnosis of ovarian carcinoma. The authors also included up to date recent information from the research performed in their own laboratory. EXPERT OPINION: The combination of CA125 with HE4 facilitates the triaging of women with a pelvic mass and detects more stage I/II tumors than CA125, the present 'gold standard', when used alone. Assaying urine for HE4 or mesothelin may detect early ovarian carcinoma more often than assaying serum. Antibodies to mesothelin and HE4 are more frequent in women with ovarian carcinoma or with certain types of infertility than in controls. No presently available biomarker or multi-marker panel lends itself to screening large populations of symptomless women to make possible detection of high grade serous ovarian carcinoma at stage I or II. The authors anticipate, within the next 5 years, that a greater emphasis will be given to the fact that the different subtypes of ovarian carcinoma represent different types of disease. Each different type of disease will require a different diagnostic approach and more efforts will focus on high grade serous ovarian carcinoma for which the clinical need is the greatest.