Working around the clock is common for many occupations, as diverse as nurses, truck drivers, physicians, steel workers, and pilots. Each shift-work profession is individual in more aspects than just work hours and individual work scenarios, each posing a different impact on the health of workers. Related health problems in shift workers, therefore, are also diverse and encompass sleep problems, metabolic and cardiovascular system disturbances, as well as cancer. Little is known about how all these individual factors influence a shift worker's health status, partly because many shift-work studies show inconsistent results. In addition, these individual factors create many methodological difficulties for researchers who investigate such work scenarios. This chapter presents examples from our laboratory and field studies of shift workers, which emphasize the importance of taking individual circumstances into account. Both study approaches, laboratory and field based, are needed to fully account for the difficulties that shift-work studies pose on both workers and researchers. Finally, understanding the mechanisms that underpin interindividual differences in response to shift work will advance our understanding of how to design better and healthier shift-work schedules in the future.