Depression is a serious condition associated with great suffering on both personal and global scales. Resilience research on depression is growing as a part of a relatively recent shift to a focus on positive health outcomes and may hold great promise for discovering new avenues to understanding, preventing, and treating depression. The current study tested the stress-inoculation hypothesis, a resilience concept that suggests that those who have experienced a moderate amount of previous life stress will be better prepared to endure future life stress. Preclinical evidence and some clinical research suggests that a moderate level of childhood adversity (CA) may better prepare an individual to be resilient to the effects of future life stress, as opposed to severe or little CA. Approximately 400 emerging adults were assessed with respect to CA, current life stress, cortisol response to an acute stressor, depressive outcomes, and positive functioning outcomes. Most generally, the stress-inoculation hypothesis was not supported by the data. Those with moderate CA did not produce a more resilient cortisol response to an acute stressor, and did not consistently report less depressive symptoms or greater levels of positive functioning when challenged by recent severe life stress. Implications for future research are discussed.