Mental illness affects every aspect of life and society, from relationships between individuals and within families, to small communities and entire polities. People with serious mental illness die decades before those without. Mentally ill people suffer daily as they struggle to function in societies that are unforgiving and uninterested in their pain. Those with serious mental illness may be incarcerated because of their sickness, they may be passed over or fired from jobs, subjected to ridicule and mockery, given little treatment or safe shelter, and violently victimized. As a result, persons with mental illness are some of the most vulnerable people in our society. And while the world is focused on the COVID-19 pandemic, it is important to remember that these facts have not changed and, in fact, the burden of mental illness continues to increase, claiming the lives of thousands of people each day who die from suicide, drug overdose, or comorbidity caused or exacerbated by psychiatric illnesses. This issue of Perspectives in Biology and Medicine offers an interdisciplinary sampling of new scholarship describing the conceptual, ethical, and policy challenges presented by the harsh reality of mental illness.