By the end of 2006, approximately 2.3 million children worldwide were living with HIV infection, representing about 15% of all HIV-infected individuals but only 5-7% of the total population of treated patients worldwide. Despite a general increase in the use of antiretroviral therapy (ART) in resource-limited settings, appropriate care and ART remain inaccessible for most of the world's HIV-infected children. ART of children is challenging because of a general lack of paediatric formulations (including tablets in paediatric strengths), limited options of drugs available for children (some have been approved only for use in adults), different viral and immunological responses, dependency on caregivers for administration of the therapy, and specific issues of toxicity in long-term therapy related to maturation and development. As in adults, nucleoside reverse transcriptase inhibitors (NRTIs) are a key component of any ART schedule in children, being the recommended 'backbone' treatment in US, European and WHO guidelines, and, indeed, NRTIs have been extensively studied in children. NRTIs are the class of antiretroviral drugs that have more drugs licensed for paediatric use and more paediatric formulations.Generally, the dual NRTI backbone treatment of combination with a non-NRTI (NNRTI) or protease inhibitor (PI) should comprise a cytidine analogue (lamivudine, emtricitabine) and a thymidine analogue (stavudine, zidovudine), guanosine analogue (i.e. abacavir), or nucleotide RTI (NtRTI; i.e. tenofovir). European and US guidelines recommend the use of triple NRTI therapy (abacavir/lamivudine/zidovudine) in children with anticipated poor adherence to other treatment regimens because of tablet burden. In conclusion, while use of ART in children needs to be dramatically increased, selecting and administering the best drug combination for children is still limited by a lack of paediatric formulations and knowledge of drug metabolism, safety and efficacy in children. NRTIs are already a key component of paediatric ART, but fixed-dose combinations and specific research in children are needed to optimise their use. In this article we review the available information to facilitate selection of the best NRTI for backbone treatment in combination ART for HIV-infected children.