<p>Life lessons from a civilization’s most consequential individuals are hard to come by and, certainly, rarely find their way into a medical journal. However, such investigations can repay study—as Plutarch’s continued popularity demonstrates. Our subjects lived before the era of medications and might today be diagnosed, not coincidentally, as having bipolar temperaments, and possibly bipolar disorder as well, and suffered severe depressions. We consider Robert Burton, Samuel Johnson, Meriwether Lewis, Winston Churchill, William Osler, and Jacques Barzun with an eye toward understanding how they were able to get the best from themselves and stimulate the most intense expression of their remarkable gifts—all the while escaping crippling depressions to which they were prone. Their insights were forged in the harsh crucible of life experience. Five of them (there appears no record of how Lewis understood his temperament) sought to pass on what they had learned, even writing about their discovered truths in similar fashion. Each found salvation in total commitment to a creative and spiritually satisfying challenge of an all-encompassing sort. Such a technique proved to be both palliative and prophylactic for reasons that, scientifically, are unclear. Some of the questions that their distinguished lives suggest are discussed.</p>