: Sepsis is a heterogeneous disease caused by an infection stimulus that triggers several complex local and systemic immuno-inflammatory reactions, which results in multiple organ dysfunction and significant morbidity and mortality. The diagnosis of sepsis is challenging because there is no gold standard for diagnosis. As a result, the clinical diagnosis of sepsis is ever changing to meet the clinical and research requirements. Moreover, although there are many novel biomarkers and screening tools for predicting the risk of sepsis, the diagnostic performance and effectiveness of these measures are less than satisfactory, and there is insufficient evidence to recommend clinical use of these new techniques. As a consequence, diagnostic criteria for sepsis need regular revision to cope with emerging evidence. This review aims to present the most updated information on diagnosis and early recognition of sepsis.