The complex biology of critical illness not only reflects the initial insult that brought the patient to the intensive care unit but also, and perhaps even more importantly, it reflects the consequences of the many clinical interventions initiated to support life during a time of lethal organ system insufficiency. The latter may amplify or modify the response to the former and are eminently amenable to modulation by changes in practice. However, they rarely figure in conceptual models of critical illness and are almost never accounted for in preclinical models of disease. In the preceding issue of Critical Care, O'Mahony and colleagues reported on an animal model in which sequential insults – low-dose endotoxin followed by mechanical ventilation – induce much greater remote organ injury than either insult alone. Although animal models are poor surrogates for clinical illness, studies such as these provide valuable platforms for probing the complex interactions between insult and therapy that give rise to the intricate biology of critical illness.