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Cytokines are molecules that play critical roles in the regulation of a wide range of normal functions leading to cellular proliferation, differentiation and survival, as well as in specialized cellular functions enabling host resistance to pathogens. Cytokines released in response to infection, inflammation or immunity can also inhibit cancer development and progression. The predominant intracellular signaling pathway triggered by cytokines is the JAK-signal transducer and activator of transcription (STAT) pathway. Knockout mice and clinical human studies have provided evidence that JAK-STAT proteins regulate the immune system, and maintain immune tolerance and tumor surveillance. Moreover, aberrant activation of the JAK-STAT pathways plays an undeniable pathogenic role in several types of human cancers. Thus, in combination, these observations indicate that the JAK-STAT proteins are promising targets for cancer therapy in humans. The data supporting this view are reviewed herein.