Biomarkers have become an integral part of the clinical decision-making process of clinicians dealing with febrile children. C-reactive protein, procalcitonin and white blood cell count are probably the most studied ones. Crucial to using biomarkers is the understanding of how a test result will alter post-test probabilities and then impact on clinical decision making. Improved analytical and computational platforms have enabled the next generation of advanced biomarker discovery studies. Promising combinations of candidate biomarkers for a diverse spectrum of febrile illnesses, such as viral and bacterial infections, have been identified using proteomics, RNA gene expression and metabolomics.