An evolutionary perspective on bipolar disorder integrates evolutionary history with psychoneuroimmune mechanisms to explain the various factors that contribute to mood changes between depression and mania. It also highlights the evolutionary novelty of many of these factors. Manic and hypomanic episodes are often triggered by stressful life events, partially because stress can impair the functioning of the internal circadian clock. Stress can also induce gut dysbiosis, low-grade systemic inflammation, and neuroinflammation. However, increased dopaminergic activity observed during mania can suppress inflammatory processes. The anti-inflammatory effect of dopamine can explain the absence of typical manifestations of sickness behavior (such as slow psychomotor activity, lethargy, weakness, and anhedonia) that characterize depression and other inflammatory states but that are absent in mania. In the depressive phase of bipolar disorder, in contrast, the dopaminergic system is downregulated, and symptoms of sickness behavior tend to be present. Astrocytes are another proximate mechanism that dysregulates circadian rhythm, leading to bipolar mood shifts via low sleep quality and quantity. The evolutionary psychoneuroimmunological model presented in this book indicates that bipolar disorder is a result of an environmental mismatch between the environments in which humans evolved and the environments and lifestyles that are typical for contemporary western populations.