Current outcome prediction in critically ill patients relies on the art of clinical judgement and/or the science of prognostication using illness severity scores. The biochemical processes underlying critical illness have increasingly been unravelled. Several biochemical markers reflecting the process of inflammation, immune dysfunction, impaired tissue oxygenation and endocrine alterations have been evaluated for their predictive power in small subpopulations of critically ill patients. However, none of these parameters has been validated in large populations of unselected ICU patients as has been done for the illness severity and organ failure scores. A simple biochemical predictor of ICU mortality will probably remain elusive because the processes underlying critical illness are very complex and heterogeneous. Future prognostic models will need to be far more sophisticated.