Depression is commonly diagnosed and treated in primary care. Recent evidence indicates that the majority of depressed patients will not fully recover with an initial antidepressant treatment. This paper reviews commonly used options for treatment after an inadequate initial antidepressant response. The alternatives range widely, and include escalating the dose of the initial antidepressant, switching to an alternative medication, combining two antidepressants with different mechanisms of action (e.g., bupropion + SSRI or mirtazapine + venlafaxine), adding other medications such as lithium or certain atypical antipsychotics (olanzapine, aripiprazole, or quetiapine) to the antidepressant, adding a natural product such as l-methylfolate or s-adenosylmethionine (SAMe), or adding cognitive behavioral psychotherapy. What agent to be used will depend on the comfort level of the primary care practitioner and the availability of Psychiatry referral. However, it is reasonable to take one or more additional steps to attempt to achieve remission. © 2013 Springer Science+Business Media New York.