The initiation of antiretroviral therapy has resulted in an impressive reduction in the rate of disease progression in AIDS and HIV-1-related deaths in children; however, there are still several major challenges to be faced in order to improve therapy. A major topic that needs to be dealt with is the establishment of the optimal dosage of antiretroviral therapy for children. This review presents the currently available peer-reviewed data on the pharmacokinetics of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion inhibitors (FIs) in children. In addition, the data are discussed in relation to the currently available European and US guidelines and the US FDA-approved drug labels. High intra- and interpatient variability in pharmacokinetics are often observed for all antiretroviral drugs. The number of children included in the pharmacokinetic studies is often small and children are often divided into divergent groups using different dosage levels and/or drug formulations. For a substantial number of antiretroviral drugs, dosage recommendations, especially for young children, are still absent in the European and US guidelines. The recommended drug dosages in the guidelines are often different from that in the officially approved drug product label. In addition, the recommended drug dosages may deviate between the European and US guidelines. Thus, while practioners aim to meet the recommendations in the official guidelines, patients may receive highly divergent dosages of medication. The high intra- and interpatient variability in pharmacokinetics of antiretroviral drugs in children hampers the application of fixed dosages of antiretroviral drugs. For PIs and NNRTIs, plasma drug levels correlate with viral suppression and drug toxicity. NRTIs are prodrugs that are intracellularly converted to their active triphosphate form and, therefore, plasma NRTI levels correlate poorly with viral suppression. Therapeutic drug monitoring of PIs and NNRTIs should be considered to optimise HIV therapy in children.