Sepsis is a severe global health challenge characterized by significant morbidity and mortality. The 2016 Sepsis-3 definition emphasizes its complexity as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Bacterial pathogens, historically dominant, exhibit geographic variations, influencing healthcare strategies. The immune system recognizes pathogen-associated molecular patterns (PAMPs), triggering innate immune responses and inflammatory cascades. Dysregulation leads to immunothrombosis, disseminated intravascular coagulation, and mitochondrial dysfunction, contributing to the septic state. Viral sepsis, historically less prevalent, saw a paradigm shift during the COVID-19 pandemic, underscoring the need to understand the immunological response. Retinoic acid-inducible gene I-like receptors and Toll-like receptors play pivotal roles, and the cytokine storm in COVID-19 differs from bacterial sepsis. Latent viruses like human cytomegalovirus impact sepsis by reactivating during the immunosuppressive phases. Challenges in sepsis management include rapid pathogen identification, antibiotic resistance monitoring, and balancing therapy beyond antibiotics. This review highlights the evolving sepsis landscape, emphasizing the need for pathogen-specific therapeutic developments in a dynamic and heterogeneous clinical setting. Sepsis remains a critical global health challenge, affecting nearly 49 million people annually and contributing to 20% of all deaths. With 20–30% of patients succumbing during the acute phase, the mortality remains unacceptably high. In addition, the risk persists even post-hospitalization, emphasizing the ongoing threat sepsis poses to global health. With the exception of the COVID-19 pandemic, bacterial pathogens are the most prevalent sepsis-causing agents, with viruses only playing a minor part. However, during the immunosuppressive phase of the disease, reactivation of latent viruses can increase mortality significantly. There is an urgent need for innovative approaches for translational sepsis models in order to be able to accurately study the pathomechanisms of sepsis in research.Sepsis is a severe global health challenge characterized by significant morbidity and mortality. The 2016 Sepsis-3 definition emphasizes its complexity as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Bacterial pathogens, historically dominant, exhibit geographic variations, influencing healthcare strategies. The immune system recognizes pathogen-associated molecular patterns (PAMPs), triggering innate immune responses and inflammatory cascades. Dysregulation leads to immunothrombosis, disseminated intravascular coagulation, and mitochondrial dysfunction, contributing to the septic state. Viral sepsis, historically less prevalent, saw a paradigm shift during the COVID-19 pandemic, underscoring the need to understand the immunological response. Retinoic acid-inducible gene I-like receptors and Toll-like receptors play pivotal roles, and the cytokine storm in COVID-19 differs from bacterial sepsis. Latent viruses like human cytomegalovirus impact sepsis by reactivating during the immunosuppressive phases. Challenges in sepsis management include rapid pathogen identification, antibiotic resistance monitoring, and balancing therapy beyond antibiotics. This review highlights the evolving sepsis landscape, emphasizing the need for pathogen-specific therapeutic developments in a dynamic and heterogeneous clinical setting. Sepsis remains a critical global health challenge, affecting nearly 49 million people annually and contributing to 20% of all deaths. With 20–30% of patients succumbing during the acute phase, the mortality remains unacceptably high. In addition, the risk persists even post-hospitalization, emphasizing the ongoing threat sepsis poses to global health. With the exception of the COVID-19 pandemic, bacterial pathogens are the most prevalent sepsis-causing agents, with viruses only playing a minor part. However, during the immunosuppressive phase of the disease, reactivation of latent viruses can increase mortality significantly. There is an urgent need for innovative approaches for translational sepsis models in order to be able to accurately study the pathomechanisms of sepsis in research.