Sepsis is a major healthcare problem from the perspective of mortality and economics. Advances in diagnostic detection of infection and sepsis have been slow, but recent advances in both soluble biomarker detection and quantitative cellular measurements promise the availability of improved diagnostic techniques. Though the promise of cytokine measurements reaching clinical practice have not matured, procalcitonin levels are currently available in many countries and appear to offer enhanced diagnostic distinction between bacterial and viral etiologies. Cellular diagnostics is poised to enter clinical laboratory practice in the form of neutrophil CD64 measurements, which offer superior sensitivity and specificity to conventional laboratory assessment of sepsis. Neutrophil CD64 expression is negligible in the healthy state. However, it increases as part of the systemic response to severe infection or sepsis. The combination of cellular proteomics, as in the case of neutrophil CD64 quantification, and selected soluble biomarkers of the inflammatory response, such as procalcitonin or triggering receptor expressed on myeloid cells (TREM)-1, is predicted to remove the current subjectivity and uncertainty in the diagnosis and therapeutic monitoring of infection and sepsis.