Sepsis in the United States has an estimated annual healthcare cost of 16.7 billion dollars and leads to 120,000 deaths. Insufficient development in both medical diagnosis and treatment of sepsis has led to continued growth in reported cases of sepsis over the past two decades with little improvement in mortality statistics. Efforts over the last decade to improve diagnosis have unsuccessfully sought to identify a "magic bullet" proteic biomarker that provides high sensitivity and specificity for infectious inflammation. More recently, genetic methods have made tracking regulation of the genes responsible for these biomarkers possible, giving current research new direction in the search to understand how host immune response combats infection. Despite the breadth of research, inadequate treatment as a result of delayed diagnosis continues to affect approximately one fourth of septic patients. In this report we review past and present diagnostic methods for sepsis and their respective limitations, and discuss the requirements for more timely diagnosis as the next step in curtailing sepsis-related mortality. We also present a proposal toward revision of the current diagnostic paradigm to include real-time immune monitoring.