Human papillomavirus (HPV) is the most common sexually transmitted infection. The implementation of primary prevention aims to reduce the burden of HPV infection and HPV-related disease. However, HPV-related diseases are still a concern, even in high-income countries. Approximately 570 000 new cervical cancer cases are diagnosed in Italy every year. Prophylactic HPV vaccines have been developed to minimize the spread of HPV. Growing evidence supports the administration of HPV vaccines (even just one dose) in reducing the prevalence of HPV infection and HPV-related disease including cancers. HPV vaccines are characterized by a high level of efficacy (>95%) in women who are naïve to HPV; however, they do not increase clearance in patients with ongoing HPV infection. With more than 200 million doses administered to date, HPV vaccines are considered to be safe and effective at preventing HPV-related infections and cancers. In this review we aim to review the current evidence regarding HPV vaccination and to describe trends in HPV vaccination coverage in Italy. In Italy, vaccination against HPV has been included in the National Immunization Plan (NIP) since 2007–2008. Using data abstracted from the Italian Ministry of Health, we analyzed changes in HPV vaccination coverage. We observed that HPV vaccines are underutilized and coverage rates are decreasing. Looking at the target population (females and males aged 11–12 years) in Italy, a decrease in coverage rates was observed. A call for action, improved HPV awareness, and education are the key elements to enhance the widespread adoption of HPV vaccination.