Interferon-α (IFNα) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumors, and melanoma. IFNα, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumor cell growth is directly suppressed by IFNα is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will review the consolidate signal transducer and activator of transcription (STAT)-dependent mechanism of action of IFNα. We will discuss data obtained by us and others on the triggering of the stress-dependent kinase pathway induced by IFNα and its correlations with the apoptotic process. The regulation of the expression of proteins involved in apoptosis occurrence will be also described. In this regard, IFNα is emerging as a post-translational controller of the intracellular levels of the apoptosis-related protein tissue transglutaminase (tTG). This new way of regulation of tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. Until today, inconsistent data have been obtained regarding the clinical effectiveness of IFNα in the therapy of solid tumors. In fact, the benefit of IFNα treatment is limited to some neoplasms while others are completely or partially resistant. The mechanisms of tumor resistance to IFNα have been studied in vitro. The alteration of JAK-STAT components of the IFNα-induced signaling, can be indeed a mechanism of resistance to IFN. However, we have recently described a reactive mechanism of protection of tumor cells from the apoptosis induced by IFNα dependent on the epidermal growth factor (EGF)-mediated Ras/extracellular signal regulated kinase (Erk) signaling. The involvement of the Ras[RIGHTWARDS ARROW]Erk pathway in the protection of tumor cells from the apoptosis induced by IFNα is further demonstrated by both Ras inactivation by RASN17 transfection and mitogen extracellular signal regulated kinase 1 (Mek-1) inhibition by exposure to PD098059. These data strongly suggest that the specific disruption of the latter could be a useful approach to potentiate the antitumour activity of IFNα against human tumors based on the new mechanistic insights achieved in the last years. © 2004 Wiley-Liss, Inc.