Combination antiretroviral therapy (ART) for the treatment of HIV infection requires sustained adherence to maintain its efficacy. Adherence to ART presents several challenges for children receiving it and for their caregivers and pediatricians. Many factors can affect adherence to ART; they can be divided into: 1) Factors related to the patient and the family; 2) Factors related to the drug/medication; and 3) Factors related to the health care system. Different strategies can be employed to overcome some of the obstacles identified in these three groups. Some of these strategies are of proven efficacy; others have been proposed and tested only in small cohorts. Tailoring ART regimen on the daily activities of the child and his/her family, coupled with an intensive education programme on adherence for child and caregivers, prior to starting the treatment is probably one of the most effective interventions. Specific medication-related problems (depending on drug pharmacokinetic and pharmacodynamic, taste and palatability, food restrictions, etc.) exist; such problems cannot be solved solely by clinicians or by families. In this area, greater commitment of the pharmaceutical industry is still needed, and innovative solutions have to be identified by clinicians in partnership with drug manufacturers. Furthermore, an “adherence strategy/programme” should be a key component of the ART delivery strategy of any institution treating HIV-infected children. Most of the necessary interventions to be included in such programmes can be easily implemented, but they require trained and committed staff (and institutions), and time to be spent with patients and their caregivers.