Palliative care (PC) providers often prescribe psychotropic medications to address psychological and physical suffering of patients with serious medical illness. Consideration must be given to the significant medical comorbidities of the patient when selecting a medication. This article seeks to provide guidance on how to safely and effectively select a psychotropic agent for depression, anxiety, and other distressing symptoms for patients with serious illness. To do so, we draw upon a team of physicians and a pharmacist with training in psychiatry and PC to highlight the "Top 10" tips for selecting a psychotropic medication to provide relief for patients with serious medical illness.