Type I interferons (IFNs) represent a group of cytokines that act through a common receptor composed by two chains (IFNAR-1 and IFNAR-2). Several in vitro and in vivo studies showed a potent antitumor activity induced by these cytokines. IFN-α, 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. IFN-α, is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-α is limited by the activation of tumour resistance mechanisms. This article reviews the current knowledge about the antitumor activity of type I IFNs, focusing on new potential strategies able to strengthen the antitumor activity of these cytokines.