The question about when to start antiretroviral therapy in HIV-1-infected patients has been debated since the discovery of the first antiretroviral agent (zidovudine) back in 1986 and has been fuelled by the introduction of highly active combined antiretroviral therapy (cART) 10 years later in 1996. The dramatic improvement in the mortality rate associated with cART supported the principle of 'hitting early and hard', but the initial enthusiasm was quickly tempered by the realization of the inconveniences and the short- to mid-term treatment-related toxicities, including lipoatrophy. In 2009, cART can be very simple and generally well tolerated. All patients with a CD4+ T cell count of <350 cells/mm(3) should receive cART. Moreover, several cohort studies have convincingly demonstrated a significant reduction of AIDS- and non-AIDS-related events when cART is initiated at >350 CD4+ T lymphocytes/mm(3), and even at >500 CD4+ T lymphocytes/mm(3). Also, cART may be considered when there are associated co-morbidities, such as hepatitis C. In addition to individual benefits, an undetectable viral load in response to cART is associated with a substantial reduction in the likelihood of HIV transmission. This can benefit seronegative sexual partners and can potentially diminish the number of new infections, especially if those infected persons unaware of their situation can be identified and advised to initiate cART. Willingness to be treated and to adhere to the prescribed medication still remains the key to success.