Though short-term stress is adaptive, long-term stress is clearly associated with disease vulnerability, including mental illness.  Despite a significant disease-related societal burden stemming from mental health disorders, there remain significant gaps in our scientific understanding of the genesis, progression, and treatment of stress-induced mental illness. These challenges include a failure to identify the "tipping point" between adaptive and maladaptive stress exposure, variable responses to stress across brain regions, and a complete lack of strategies to prevent mental illness.  I will discuss these and other challenges in light of our recent discovery and characterization of a previously unrecognized branch of the stress response, mediated by the hormone ghrelin.  I will show that stress-related increases in ghrelin drive maladaptation in multiple, parallel neural systems and reveal newly uncovered biological mechanisms by which these changes occur.  I will also discuss our work extending these findings to humans, and the exciting and novel  implications for the treatment of disease in patient populations.