Recognizing depression in multiple sclerosis (MS) patients can be challenging because of the overlap of symptoms between these psychiatric and neurologic illnesses. Mounting evidence suggests that depression in MS is immune-mediated and the result of brain inflammation rather than the patient's environmental situation. The first randomized double-blind placebo-controlled trial of an antidepressant to treat MS depression involved five weeks of desipramine compared to placebo. Depression is associated with immune dysregulation, including elevated proinflammatory cytokines. Rehabilitation and recovery from the disability associated with MS relapses or progression can constitute a painstaking and laborious journey. The Goldman Algorithm based upon evidence presented at the Goldman Consensus Conference aims to establish a standard of care for neurologists to identify and treat major depression in MS patients. Depression is one of the most treatable comorbidities of MS, with the usual expectation that individuals who receive adequate treatment will make a complete recovery.