Interferons (IFNs) remain the most broadly active cytokines for cancer treatment, yet ones for which the full potential is not reached. IFNs have impacted positively on both quality and quantity of life for hundreds of thousands of cancer patients with chronic leukemia, lymphoma, bladder carcinoma, melanoma, and renal carcinoma. The role of the IFN system in malignant pathogenesis continues to enhance understanding of how the IFN system may be modulated for therapeutic advantage. Reaching the full potential of IFNs as therapeutics for cancer will also result from additional understanding of the genes underlying apoptosis induction, angiogenesis inhibition, and influence on immunologic function. Food and Drug Administration (FDA) approval of IFNs occurred less than 20 years ago; after 40 years, third-generation products of early cytotoxics, such as 5- fluorouracil (5FU), are beginning to reach clinical approval. Thus, substantial potential exists for additional application of IFNs and IFN inducers as anticancer therapeutics, particularly when one considers that their pleiotropic cellular and molecular effects have yet to be fully defined.