In an effort to understand how environmental experiences contribute to risk for major depression (MD), we conducted joint autobiographical interviews with 14 pairs of monozygotic twins (mean age 51.2) rigorously discordant for a lifetime history of MD. Twelve of the pairs could be sorted into four broad categories. In two pairs, discordance was associated with a single traumatic event occurring to the affected twin. In seven pairs, the well twin had one stable, long-term, successful romantic relationship, whereas the affected co-twin had romantic reversals one or more of which precipitated depressive episodes. These pairs varied in the degree to which the romantic problems seemed to arise from bad luck or poor choices. In one pair, occupational difficulties were strongly related to discordance in experiences with MD. In two pairs, several mechanisms seemed to be at work. Discordance in the quality of intimate love relationships was the most common etiological factor revealed by interview in these discordant pairs, with single dramatic events and occupational problems being considerably rarer. Even in this best of natural experiments, the causal interrelationship between personality, environment and depressive episodes was not always clear. Many pairs illustrated the protective effects of planfulness and the malignant effect of cumulative continuity where early difficulties in relationships shaped the subsequent life course. These results speak both to the importance of environmental influences on human well-being and psychopathology, and the complexity of the causal paths underlying their effects.