The American Cancer Society estimates that by 2023, about 13,960 new cases of invasive cervical cancer will be diagnosed and that 4310 women will die of cervical cancer. About 79 million Americans are infected with HPV. The Bethesda system for reporting cervical cytology has forged our understanding of HPV biology and provides an infrastructure for systematic and evidence-based cervical cancer screening and management guidelines. Direct detection of HPV, e.g., by testing for HPV DNA or HPV-produced mRNA of known oncogenic genes, has found its place in new screening strategies. HPV 16 and 18, being the most prevalent and most oncogenic HPV types, resulted in the need for HPV genotyping. HPV DNA detection-based methods are currently the most suitable way of approaching this issue, leading to the development of different platforms. Testing for HPV status in formalin-fixed, paraffin-embedded histological samples, mainly for prognostic reasons (but also as an aid in differential diagnosis), is mainly done using either DNA in situ hybridization or p16 immunohistochemistry.