Depression is a major public health problem and a common cause of disability. To help physicians choose among available treatment options, the American College of Physicians recently issued a guideline titled “Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients with Major Depressive Disorder.” The evidence review done for the guideline found no statistically significant difference in the efficacy of second-generation antidepressants (SGAs) versus most other treatments for this disorder. However, rates of adverse events and discontinuation were generally higher in patients treated with SGAs. This Beyond the Guidelines reviews the guideline and includes a discussion between 2 experts on how they would apply it to a 64-year-old man with depression who is reluctant to begin medication. They review the data on which the guideline is based, discuss the limitations of applying the data to real-world settings, review how they would incorporate patient preferences when making treatment decisions, and outline options for patients in whom first-line therapy has failed.