Recent advances in our understanding of the molecular biology of vulvar squamous cell carcinoma (VSCC) provide insight into the future management of VSCC with molecular targeted therapies and offer an opportunity to improve the treatment of this forgotten women's cancer.The incidence of vulvar squamous cell carcinoma (VSCC) has been on the rise since the 1990s. There has been no new treatment for advanced and recurrent disease in decades, with most women succumbing to the disease. Despite two distinct etiologies of VSCC, human papillomavirus (HPV)-associated and HPV-independent disease, there is no difference in therapeutic options. A literature review was carried out by searching EMBASE and Medline databases between January 1990 and March 2016 by pairing the keywords of vulvar carcinoma, vulva cancer, vulvar and vulva with molecular markers involved in the cell cycle, apoptosis and angiogenesis. Molecular targets of prognostic significance were identified and targeted agents of therapeutic relevance to both HPV-independent and HPV-associated VSCC were then reviewed. Recent advances in our understanding of the molecular biology of VSCC provide insight into the future management of VSCC with molecular targeted therapies. Aberrant cell cycle activity is common in both HPV-associated and HPV-independent VSCC and is characterized by overexpression of p53, Rb and cyclin D1, supporting targeting of these protein products and their downstream pathways. Extracellular regulators of cellular activity, such as EGFR, as well as inhibitors of angiogenesis are being clinically evaluated in VSCC. HPV-independent VSCC is characterized by actionable mutations, including PI3K, CDKN2A and PTEN. In HPV-associated disease, therapeutic vaccines targeting the E6 and E7 HPV oncogenes and immune-based therapies are under investigation. There has been a paucity of clinical trials in recent years in this neglected women's cancer. Directed therapy against cell cycle regulatory molecules and extracellular proteins and the inhibition of angiogenesis are of broad therapeutic relevance in VSCC. Therapeutic strategies that target actionable mutations should be explored. In HPV-associated VSCC, novel treatments that exploit the virology of HPV and/or enhance the host immune response merit further study.