Multiple trauma leads to a deterioration of the immune system. On the one hand, hyperinflammation mediates remote organ damage and may lead to multi-organ failure. On the other hand, immunosuppression develops and promotes an enhanced risk to acquire infectious complications after trauma. The mechanisms that underlie these opposing consequences of trauma are not yet completely understood. There is increasing evidence that endogenous danger signals that derive from destroyed tissues play a role in trauma-induced immune dysfunction. Here, we give an overview on the common animal models that are used to investigate trauma-induced pathology, potential signals and cellular mechanisms that support the imbalance between inflammation and counter-regulation after trauma.