Depression is common in serious illness, yet traditional antidepressants have a delayed onset. Psychostimulants offer potentially rapid symptom relief, but their evidence base for depression, especially in medically complex patients, remains unclear. In this Palliative Care Rounds, we review the evidence for the use of psychostimulants as monotherapy or augmentation for major depressive disorder, including trials enrolling patients with cancer or other serious illnesses. Evidence for monotherapy is weak: meta-analyses of small, methodologically limited trials suggest modest benefit compared with placebo. Augmentation studies demonstrate statistically significant but clinically small effects. Data on people with serious illnesses is limited to a small number of heterogeneous trials with inconsistent findings. Overall, psychostimulants have limited evidence for depression in serious illness, particularly as monotherapy. Given evidence for alternative rapid-acting interventions, such as ketamine/esketamine or second-generation antipsychotic augmentation, psychostimulants should be used sparingly and reserved for specific scenarios (e.g., comorbid attention-deficit/hyperactivity disorder or prior robust response).