Human injury is associated with inflammatory responses that are modulated by the acute and chronic activity of endogenous factors and exogenous interventions. A characteristic feature of chronic, severe inflammatory states is the diminished signal output variability of many organ systems, including innate immune responsiveness and endogenous neural and endocrine-mediated functions. The attenuation of signal/response variability and integration of feedback capacity may contribute to systemic and tissue-specific deterioration of function. Some well-intentioned therapies directed toward support of systemic and tissue functions may actually promote the loss of system(s) adaptability and contribute to adverse outcomes in severely stressed patients. In vivo and in silico models of stress, injury, and infection have yet to fully define the influences of ongoing stressful stimulae as well as genetic variation and epigenetic factors in the context of an evolving inflammatory state. Experimental and human models incorporating variable, antecedent stress(es) and altered neuroendocrine rhythms might approximate the altered adaptability in immune and organ function responses. Such models may also provide insights into the salient mechanisms of risk and outcome more precisely than do the constrained study conditions of current animal or human models of systemic inflammation.