Trauma, sepsis, and surgery are associated with global hypercatabolism and a negative nitrogen balance. When critical illness is prolonged the relentless loss of lean tissue becomes functionally important. Protein catabolism in the critically ill patient is associated with complex changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Many small clinical studies indicate that treatment with recombinant human (rh) GH would be a safe and effective means of limiting the deleterious effects of the catabolic response. Unexpectedly, however, two large prospective randomized controlled trials (PRCTs) demonstrated that administration of rhGH to long-stay critically ill adults increases morbidity and mortality. Some progress has been made in understanding the mechanisms underlying this observation.