Vulvar cancer affects 2.5 per 100,000 women per year and represents 0.3% of all new cancer cases in the United States. It is primarily a disease of elderly women, with those between the ages of 75 and 84 most commonly affected. The majority of vulvar cancers (90%) are squamous cell carcinomas (SCC). In contrast to the cervix, where virtually all squamous neoplasia is driven by human papillomavirus (HPV) infection, two distinct pathways to invasive squamous cell carcinoma are recognized in the vulva: the HPV-associated and the HPV-independent pathway. These pathways differ with respect to epidemiological, clinical, histopathological, immunophenotypic, molecular, and prognostic characteristics. HPV-associated vulvar SCC arises typically in younger women, in a background of a high-grade squamous intraepithelial lesion (HSIL) and carries a good prognosis. Similarly to SCC in the head and neck, patients with HPV-associated vulvar SCC demonstrate better response rates to radiation and chemotherapy. HPV-independent, TP53-wild-type vulvar SCC arises in older women, in a background of precursors designated as DE-VIL/VAAD/VAM/vaVIN and has an intermediate prognosis. This is in contrast to HPV-independent, TP53-mutant vulvar SCC, which occurs in older women with a history of lichen sclerosus and differentiated VIN, and exhibits a poor prognosis.