Depression in serious illness is common, disabling, and often requires rapid improvement. Traditional antidepressants may take weeks to work, whereas second-generation antipsychotics (SGAs) have evidence for faster onset and robust augmentation effects in general psychiatric populations. In this Palliative Care Rounds, we review the general psychiatric and serious illness-specific evidence for the use of SGAs as monotherapy and augmentation therapy for depression. In the psychiatric literature, SGA augmentation improves response and remission rates (odds ratios 1.34-2.93; needed to treat 7-13), with onset of improvement within 1-2 weeks. Monotherapy is less well tolerated and not guideline-recommended. No randomized controlled trials have evaluated SGAs specifically for depression in serious illness, but numerous cancer trials support their safety for nausea, appetite, and other symptoms. Despite the absence of serious illness-specific psychiatric trials, SGAs have the strongest evidence base among augmentation options and may offer meaningful benefits when prognosis or symptom severity necessitates rapid improvement. Low-dose augmentation should be considered early, rather than only after multiple failed antidepressants, particularly when SGAs can also target co-occurring physical symptoms relevant to palliative care.