The complexity of the systemic inflammatory response and the lack of a treatment breakthrough in the treatment of pathogenic infection demand that advanced tools be brought to bear in the treatment of severe sepsis and trauma. Systems medicine, the translational science counterpart to basic science's systems biology, is the interface at which these tools may be constructed. Rapid initial strides in improving sepsis treatment are possible through the use of phenomenological modelling and optimization tools for process understanding and device design. Higher impact, and more generalizable, treatment designs are based on mechanistic understanding developed through the use of physiologically based models, characterization of population variability, and the use of control-theoretic systems engineering concepts. In this review we introduce acute inflammation and sepsis as an example of just one area that is currently underserved by the systems medicine community, and, therefore, an area in which contributions of all types can be made.