Sepsis is a complex syndrome triggered by infection and characterized by systemic deregulation of immune and inflammatory pathways. It is a major cause of death worldwide and results in the widespread use of antibiotics and substantial health care costs. In a vicious circle, sepsis treatment promotes the emergence of highly virulent and resistant pathogens and devastating nosocomial infections. Sepsis is a heterogeneous disease affecting many people worldwide. Because individual patients have different inflammatory responses and unique profiles of immune activation against pathogens, the most effective way to advance the treatment of sepsis is probably through a tailored approach. The advent of high-throughput technologies and the remarkable progress in the field of bioinformatics has allowed the subclassification of many pathological conditions. This has potential to provide better understanding of life-threatening infections in people. The study of host factors, however, needs to be integrated with studies on bacterial signaling in both symbiotic and pathogenic bacteria. Sepsis is certainly the sum of multiple host-microbial interactions and the metagenome should be extensively investigated. Personalized medicine is probably the only strategy able to deconstruct and reassemble our knowledge about sepsis, and its use should allow us to understand and manipulate sepsis as a wide, interconnected phenomenon with myriad variables and peculiarities. In this study, the recent advances in this area, the major challenges that remain, and the reasons why the septic patient should be approached as a superorganism are discussed.