I recently sat at the bedside of a young man who was lost in the black corridors of deep depression. His recalcitrant depression failed to respond to any therapy and made it impossible to work and distanced him from friends and family. He felt alienated and isolated and abandoned from all forms of support, including a cumbersome health care system and providers whose compassion could not be accessed because it was curbed by bureaucracy. Nurse practitioners (NPs) working in primary care have seen glimpses of these conditions in many of their patients. A serious mental illness is reported to affect 6.3% of all U.S. adults. According to the 1999 World Health Organization global burden of disease study, severe mental illnesses (bipolar disorder, schizophrenia, severe major depression, and others) collectively account for more than 15% of the overall burden of disease from all causes. This same report finds that major depression is the leading cause of disability worldwide among persons 5 years and older. These serious mental health problems take a significant toll on individuals, families, and society. Depression and other mental illnesses also negatively impact the economy due to diminished productivity and increased use of health care resources. Society and government have failed to adequately address these problems and these vulnerable patients remain suffering and at risk, many times on the extreme margins of the health care system itself. Both psychotherapy and pharmacotherapy are critical to the treatment of serious mental illness. Pharmacotherapy in some patients shows efficacy in treating positive psychotic symptoms (delusions, hallucinations, disorganized thinking, and catatonic behavior). Drugs may also improve, to a limited extent, negative symptoms (alogia, affective blunting, anhedonia, amotivation, and attentional impairment) and reduce the risk of relapses and hospitalizations. But there are limitations to drug treatment, and there are no perfect drugs. Adverse effects are associated with a poor treatment response of negative and cognitive symptoms, with high nonadherence rates and inadequate functional improvement. Partial adherence and nonadherence are very common in serious mental illness and are associated with relapses and hospitalizations. Medication nonadherence rates may be as high as 60%. Even with adequate drug therapy, roughly 30% of individuals with positive psychotic symptoms respond partially or not at all, and negative symptoms and cognitive symptoms often do not adequately respond to pharmacotherapy. Additionally, symptomatic improvement may not mean functional improvement. Even worse, patients with serious mental illness have a lowered life expectancy and often die about 9 years earlier compared to the general population because of higher medical comorbidity, increased risk of suicide, toxicity from psychotropic medications, and other factors. Vagaries in our reimbursement system make it difficult for patients who have urgent mental health problems to see primary care providers and mental health providers on the same day. Thus, integration of more mental health diagnosis and treatment skills into primary care services is essential. To this end, we hope that this issue of JNP, with its focus on mental health issues, will stimulate NPs to develop greater knowledge and skills to help meet these desperate challenges.