Shift work is commonly associated with disturbed life rhythms, resulting in chronic exposure to circadian desynchronization and sleep restriction. Epidemiological data have shown that shift workers are at an increased risk of cardiovascular disease and breast cancer. In this review, we will explore how observed increases in neuroendocrine stress, non-specific immune responses and pro-oxidative status could act as biological mediators for these damaging health risks in shift workers. To explain these risks, compelling evidence from laboratory studies links circadian misalignment but also sleep restriction to disruptions in the neuroendocrine, immune and oxidative stress systems. Assessment of neuroendocrine, oxidative and immune stress in the shift worker population is still a limited and novel field, which may have considerable clinical relevance. Finally, we will consider the potential benefits of a countermeasure, such as napping, in minimizing the neuroendocrine and immune stress and cardiovascular risk imposed by shift work.