The need for 24-h operations creates nonstandard and altered work schedules that can lead to cumulative sleep loss and circadian disruption. These factors can lead to fatigue and sleepiness and affect performance and productivity on the job. The approach, research, and results of the NASA Ames Fatigue Countermeasures Program are described to illustrate one attempt to address these issues in the aviation environment. The scientific and operational relevance of these factors is discussed, and provocative issues for future research are presented.