Sepsis is a life-threatening condition arising from a dysregulated host response to infection. Current therapies rely on pathogen eradication and support of dysregulated organ functions. Adjunctive therapies addressing the failing host response are in their infancy. Two current developments, i.e. i) phenotyping and ii) introducing disease tolerance as a complementary coping mechanism besides resistance contributed to conceptual progress in understanding the syndrome. Emerging clinical evidence - albeit scarce – will be summarized by placing it into the context of evolutionary ecology and stress biology. As a result the talk aims to pinpoint open questions and blind spots regarding the complexity of sepsis and introduces current avenues for translational research. Moreover, we challenge the notion that disease tolerance and resistance are unconnected, opposing response patterns. Instead, we propose to view resilience as a collective term that comprises the sum of both defence traits with fundamental implications for the design of clinical sepsis trials.