Human papillomavirus (HPV), the known cause of cervical cancer, is found in essentially all cervical cancer specimens. Infection with high-risk HPV genotypes carries the greatest risk of viral persistence and the potential to develop precancerous lesions or cervical cancer. Identifying women infected with HPV 16 and/or 18, the two genotypes most commonly found in cervical cancer, helps further stratify women for either immediate referral to colposcopy or repeat cytological and HPV DNA testing in 12 months. Genotyping additional, less carcinogenic HPV types may be of limited clinical utility. Detection of multiple individual genotypes may capture a greater percentage of those with the potential to develop cervical disease. However, the advantage of individual detection must be weighed against the potential error of multiple measurements. In order for genotyping tests to have clinical benefit in patient management, the Centers of Medicare and Medicaid Services Divisions of Laboratory Services have set forth a rigorous clinical validation procedure. This procedure addresses the quality process, characteristics and specifications of the assay, comparison of the test/device to existing tests/devices, technical aspects, and other assurances that guarantee the test/device will meet all performance requirements of the US Food and Drug Administration (FDA). Currently, only the Cervista® HPV 16/18 genotyping test is approved by the FDA and recommended for clinical use in published guidelines. This manuscript reviews the current best practices for the development and use of HPV genotyping tests.