Purpose of Review: Early identification of infection in the critically ill patient and initiation of appropriate treatment is key to reducing morbidity and mortality. On the other hand, the indiscriminate use of antimicrobials leads to harms, many of which may be exaggerated in the critically ill population. The current method of diagnosing infection in the intensive care unit relies heavily on clinical gestalt; however, this approach is plagued by biases. Therefore, a reliable, independent biomarker holds promise in the accurate determination of infection. We discuss currently used host biomarkers used in the intensive care unit and review new and emerging approaches to biomarker discovery. Recent Findings: White cell count (including total white cell count, left shift, and the neutrophil-leucocyte ratio), C-reactive protein, and procalcitonin are the most common host diagnostic biomarkers for sepsis used in current clinical practice. However, their utility in the initial diagnosis of infection, and their role in the subsequent decision to commence treatment, remains limited. Novel approaches to biomarker discovery that are currently being investigated include combination biomarkers, host 'sepsis signatures' based on differential gene expression, site-specific biomarkers, biomechanical assays, and incorporation of new and pre-existing host biomarkers into machine learning algorithms. Summary: To date, no single reliable independent biomarker of infection exists. Whilst new approaches to biomarker discovery hold promise, their clinical utility may be limited if previous mistakes that have afflicted sepsis biomarker research continue to be repeated.