Sepsis, an innate immunological response of systemic inflammation to infection, is a growing problem worldwide with a relatively high mortality rate. Immediate treatment is required, necessitating quick, early and accurate diagnosis. Rapid molecular-based tests have been developed to address this need, but still suffer some disadvantages. The most commonly studied biomarkers of sepsis are reviewed for their current uses and diagnostic accuracies, including C-reactive protein, procalcitonin, serum amyloid A, mannan and IFN-γ-inducible protein 10, as well as other potentially useful biomarkers. A singular ideal biomarker has not yet been identified; an alternative approach is to shift research focus to determine the diagnostic relevancy of multiple biomarkers when used in concert. Challenges facing biomarker research, including lack of methodology standardization and assays with better detection limits, are discussed. The ongoing efforts in the development of a multiplex point-of-care testing kit, enabling quick and reliable detection of serum biomarkers, may have great potential for early diagnosis of sepsis.