The current paradigm in psychiatry sees bipolar disorder as a highly heritable disorder with environmental factors playing only a small role in its development. As bipolar disorder has been found to be rare among people with traditional lifestyles (e.g., hunter-gatherers, Old Order Amish, and Hutterites) and more common in people who have adopted Western lifestyles, it is possible that this mental disorder is the result of a mismatch between our evolutionary and current environments. In this chapter, we present a psychoneuroimmunological explanation for bipolar disorder based on evolutionary psychology, which highlights the role of low-grade inflammation and chronic stress associated with Western lifestyles as the main triggering factors linked to this mental disorder. The malfunctioning of the internal clock and alterations in the gut microbiota are also discussed. We conclude this chapter by offering evidence about how lifestyle changes may improve bipolar disorder symptoms by lowering stress and inflammation.