Drug development represents a significant challenge in patients with advanced non-small cell lung cancer and poor performance status (PS) because of the short survival time of these patients and heterogeneity in the cause of poor PS. Historically, these patients have been excluded from clinical trials. However, there is now evidence that certain treatments can produce responses and increase survival in patients with poor PS. Several clinical trials have been conducted recently to investigate treatment options in these patients. This article reviews the need for such trials, the potentially greater risks with evaluating new drugs in such patients, recommendations for designing trials in the population, and the results in recently completed and ongoing clinical trials designed specifically for the PS2 population.