This article reports on qualitative research investigating key challenges and barriers towards human papillomavirus (HPV) vaccine introduction in the Western Cape Province, South Africa. A total of 50 in-depth interviews and 6 focus groups were conducted at policy, health service and community levels of enquiry. Respondents expressed overall support for the HPV vaccine, underscored by difficulties associated with the current cervical screening programmes and the burgeoning HIV/AIDS epidemic in South Africa. Overall poor community knowledge of cervical cancer and the causal relationship between HPV and cervical cancer suggests the need for continued education around the importance of regular cervical screening. The optimal target populations for HPV vaccination was influenced by the perceived median age of sexual activity in South African girls (9-15 years), with an underlying concern that high levels of sexual abuse had significantly decreased the age of sexual exposure suggesting vaccination should commence as early as 9 years. Vaccination through schools with the involvement of other stakeholders such as sexual and reproductive health and the advanced programme on immunization (EPI) were suggested. Opposition to the HPV vaccine was not anticipated if the vaccine was marketed as preventing cervical cancer rather than a sexually transmitted infection. The findings assist in identifying potential barriers and facilitating factors towards HPV vaccines and will inform the development of policy and programs to support HPV vaccination introduction in South Africa and other African countries.