The prevailing paradigm used by most researchers and physicians to understand depression appears myopic and deficient, and the treatments derived from it are ineffective. A broader perspective is required for understanding why people in contemporary societies are vulnerable to chronic depression. Evolutionary psychoneuroimmunology synthesizes insights from evolutionary biology, evolutionary psychiatry, neuroscience, immunology, and psychology to provide a broad scientific framework for understanding the relatively high prevalence of depression in people with contemporary western lifestyles. A range of findings indicates that the mismatch between the environments in which Homo sapiens evolved and the environments it currently habits – characterized by sedentary lifestyles, obesogenic diets, fragmented communities, loneliness – contributes in several ways to depression prevalence in contemporary societies. Understanding depression in contemporary Homo sapiens requires not just analyzing the proximate mechanisms contributing to it, such as chronic stress, poor diet, and low-grade systemic inflammation, but also the evolutionary question of why a mind that has undergone hundreds of thousands of years of evolution can be so vulnerable to such severe and debilitating mental health problems. Tinbergen’s four questions, a fundamental conceptual framework used in ethology, evolutionary biology, and evolutionary psychology, organizes these different levels of analysis in a coherent framework for this book.