Since the introduction of zidovudine into HIV clinical practice in 1985, the history of antiretroviral treatment has been started. Even in well controlled patients with HIV loads under the detection limit for many years, viral load rebound could occur followed by CD4 cell count decline, if the antiretroviral treatment is interrupted. Because life-long treatment seems inevitable, long-term safety has been an important issue. During these 25 years, not only antiretroviral potency but also long-term tolerability is one of the main foci of the development of new antiretroviral agents. A particular drive to the once-daily single-tablet regimen has been seen over the last few years.