Human papillomavirus (HPV) is an important cause of anogenital and oropharyngeal cancers, anogenital warts, and recurrent respiratory papillomatosis. Beginning in 2019, US guidelines recommend shared clinical decision-making (SCDM) for HPV vaccination among mid-adults (27–45 years). We conducted a narrative review of existing literature on HPV vaccination in mid-adults. Available evidence demonstrates that HPV vaccination in mid-adults is safe, efficacious, and likely to benefit both HPV-naïve mid-adults and those with previous infections. However, gaps in knowledge related to HPV vaccination have been identified among clinicians and mid-adult patients. Universal mid-adult HPV vaccination in the United States could avert 20,934–37,856 cancer cases over 100 years, costing $141,000–$1,471,000 per quality-adjusted life-year gained. Wide variation in these estimates reflects uncertainties in sexual behavior, HPV natural history, and naturally-acquired immunity. Greater awareness among clinicians and mid-adult patients and broad implementation of SCDM may accelerate progress towards eliminating HPV-associated cancers and other diseases