The prevalence of HIV in young South African women aged 20–24 years is three times higher than that in their male counterparts. Young South African women are a key population group that contributes to 30% of all new infections in the country, highlighting the need for effective HIV prevention strategies in this population. Although HIV oral pre-exposure prophylaxis (PrEP) has proven effective in several clinical trials, vaginal and oral PrEP have failed in studies involving women in South Africa. In particular, adherence to PrEP has been low in clinical trials. HIV prevention strategies applied in clinical trial settings of young South African women can lack the cultural, socioeconomic, and historical background knowledge and insight to cater for the specific needs of this population. A PrEP panacea might, therefore, not be an achievable goal.