The availability of more than 20 drugs for the treatment of HIV infection, and the success of the current antiretroviral regimens, should not overlook the difficulty of long-term maintaining the control of viral replication. The therapy needs to be continued for decades, if not for lifetime, and there are clear evidences that, even in patients fully suppressed for many years, HIV starts again its replication cycles in case antiviral pressure is removed. The development of resistance is a natural event at the time of virological failure, that needs to be taken into account in the global strategy against HIV in each particular patient. Taking all together, therapeutic regiments must be embedded, since the beginning, in a long-term strategy whose main task is the stable control of the replication of HIV. To do so, the choice of the first antiviral regimen has to be highly appropriate to keep the virus in check, and at the same time maintain future therapeutic options. Change of therapy at the time of failure has to be also appropriate, in term of timing, diagnostic strategy, and selection of drugs. Under these circumstances, the use of protease inhibitors in the first line acquires a strong rationale, that balances the greater pure potency of non-nucleoside reverse transcriptase inhibitors (NNRTI), and makes them a valuable options for many patients that need to start antiviral therapy.