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Sepsis occurs yearly in 48.9 million people worldwide of whom 11 million will die. Sepsis is defined as a life-threatening dysregulated reaction of the body in response to a bacterial infection, leading to organ dysfunction. The Surviving Sepsis Campaign made numerous recommendations for sepsis diagnosis and treatment using an evidence-based medicine approach. Frequently, levels of evidence of these recommendations are poor and lack clear clinical guidance.  Interestingly, these guidelines strongly recommend, with a moderate quality of evidence, screening of nosocomial sepsis in acutely ill hospitalized high-risk patients. The definition of acutely ill and high-risk patients is not specified, nor it is indicated which tools should be used. The diagnosis of infection and the subsequent administration of antibiotics relies solely on rapid clinical assessment, as recommended by the Best Practice Statement. Again, the elements used for clinical assessment are poorly defined, encompassing patient history, clinical examination, and unspecified tests for both infectious and non-infectious causes of acute illness. In the real world and based on these recommendations, only 30 to 40% of empiric broad-spectrum antibiotic administrations are appropriate, contributing to the emergence of antimicrobial resistant bacteria, toxicity related to antibiotic administration, and costs. The aim of this review article is to show that the use of biomarkers, such as the Pancreatic Stone Protein, could be the specific tests and tools to help the clinician to diagnose and manage sepsis. Over 600 peer-reviewed publications have studied the physiology of Pancreatic Stone Protein and more than 50 evaluated its usefulness to screen for the development of nosocomial sepsis and diagnose sepsis.