The introduction of tenofovir (TFV) alafenamide (TAF) into clinical practice will be a further revolution in antiretroviral therapy. Currently available HIV-1 regimens are wide enough to allow diversified usage in different settings. Despite the fact that TAF is not capillary accessible, even in industrialized countries, ultimate International Guidelines have already included TAF in backbone or in single-tablet regimens. Due to a better safety profile, TAF will progressively replace TFV disoproxil fumarate, both in naïve and experienced patients. However, therapeutic innovations have to deal with budget constraints and different global spending-review patterns. The aim of this article is to give a comprehensive agenda of TAF use in naïve and experienced HIV-1 infected patients, providing a full review of the studies present in the literature and contextualizing these findings into daily clinical practice.