The primary objective of antiretroviral therapy is to suppress viral replication as soon as possible, as much as possible and for as long as possible, a concept so clearly emphasized by David Ho in 1995: "Treat HIV early and hard!". That, however, seems an ideal objective by a number of reasons, recently recognized as fundamental: unavailability of treatments able to eradicate the infection, difficulty to reach compliance to HAART (Highly Active Antiretroviral Therapy), emergence of drug resistance and cross-resistance. (Cross)-resistance in particular has the potential both to waste future therapeutic options and to be transmitted during HIV infection. Therefore, HIV pharmacoresistance has to be considered one of the most challenging focal point in research on antiretroviral therapy. Understanding of causes, evolutionary patterns and consequences of resistance in terms of viroimmunological and clinical response appears inescapable to strategically plan and monitor treatment. Rather than to eradicate the infection with regimens more and more hard but more and more difficult to comply with, the realistic approach is to construct a strategic therapeutic itinerary tailored to the bio-psycho-social patient conditions and to the saving of therapeutic options. The latter means the rational sequencing of the drug employment for a long-term therapy, potentially life-long.