Sepsis, a condition characterized by life-threatening organ dysfunction due to a dysregulated host response to infection, significantly impacts global health, with mortality rates varying widely across regions. Traditional therapeutic strategies that target hyperinflammation and immunosuppression have largely failed to improve outcomes, underscoring the need for innovative approaches. This review examines the development of therapeutic agents for sepsis, with a focus on clinical trials addressing hyperinflammation and immunosuppression. It highlights the frequent failures of these trials, explores the underlying reasons, and outlines current research efforts aimed at bridging the gap between theoretical advancements and clinical applications. Although personalized medicine and phenotypic categorization present promising directions, this review emphasizes the importance of understanding the complex pathogenesis of sepsis and developing targeted, effective therapies to enhance patient outcomes. By addressing the multifaceted nature of sepsis, future research can pave the way for more precise and individualized treatment strategies, ultimately improving the management and prognosis of sepsis patients.