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 (ORs 1.34-2.93; NNT 7-13), with onset of improvement within 1-2 weeks. Monotherapy is less well tolerated and not guideline-recommended. No RCTs 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.