There is an increasing evidence that survivors of critical illness suffer from impaired health-related quality of life. There are relatively few studies that have evaluated the effect of interventions in clinical trials to improve these long-term outcomes. Studies to improve long-term outcomes after critical illness face many of the same challenges encountered in studies designed to improve shorter term outcomes in the intensive care unit. These include an incomplete understanding of the causal mechanisms involved in post-intensive care unit impairment, trouble in identifying patients ill enough to benefit from an intervention but whose impairment is not fixed, and identifying proper outcome variables. There are, however, unique challenges to clinical trials including bias from competing mortality and incomplete follow-up. Research interest in developing interventions to improve long-term outcome after critical illness is in its infancy and it is too early to make strong clinical recommendations. Multiple potential treatment areas exist, both within the intensive care unit and after patients leave the hospital, for intensivists to target. Those interested in this area should collaborate to build on the lessons from effective multidisciplinary programs developed to treat other diseases.