Interferon (IFN)-alpha has demonstrated antitumor activity in a variety of solid and hematologic malignancies, including metastatic renal cell carcinoma. Pegylation, the process of combining a polyethylene glycol moiety to a biologic protein, substantially changes the pharmacokinetic profile of a drug, resulting in prolongation in half-life, increased area under the curve and, in some cases, improved efficacy. Pegylated IFN-alpha has been evaluated in chronic hepatitis C, chronic myelogenous leukemia and most recently in metastatic renal cell carcinoma. Registrational studies of pegylated IFN-alpha2a (PEGASYS) and pegylated IFN-alpha2b (PEG Intron) in patients with hepatitis C demonstrated greater efficacy with similar safety and tolerability to nonpegylated IFNs, with the advantage of less frequent administration. Studies evaluating these agents in the treatment of metastatic renal cell carcinoma and other cancers are ongoing.