Considerable data demonstrate the high prevalence of symptoms of depression in patients with a wide variety of neoplastic disorders. Moreover, the dire consequences of these depressive symptoms in cancer patients have been well documented. Recent conceptual developments in the potential contributing mechanisms include increasing appreciation of the possibility that behavioral alterations in cancer patients may represent a "sickness syndrome" that results from activation of the inflammatory cytokine network. This sickness syndrome, which has been well documented in patients and laboratory animals exposed to inflammatory cytokines, includes symptoms that overlap with those seen in major depression. Conceptualizing these symptoms as components of cytokine-mediated sickness behavior has several important, and potentially novel, implications, including 1) an expansion of the neurobehavioral symptoms that are relevant to diagnosis and treatment; and 2) an increased appreciation of the potential diagnostic utility of peripheral markers of inflammation, as well as cytokine-related neurocircuitry alterations as defined by brain imaging. Treatment implications focus on the pathways by which inflammatory cytokines influence behavior, including therapeutic targets such as the inflammatory cytokines themselves, corticotropin-releasing hormone, and monoaminergic neurotransmitters and their precursors. Finally, recent data suggest that aggressive treatment strategies initiated before inflammation-inducing cancer treatments might prevent behavioral alterations, including depression, before they occur.