Type I interferons (IFNs) are pleiotropic cytokines that exert multiple effects on normal and tumor cells. These effects are supposedly mediated through the stimulation of several signal transduction pathways by type I IFNs. These include the well-studied canonical Jak-Stat pathway, largely responsible for the antiviral and growth-inhibitory activities of IFNs, as well as the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, whose importance in IFN-induced biologic outcomes has not been precisely established. One of the effects of type I IFNs on tumor cells is the induction of programmed cell death, apoptosis, which has been studied extensively over the last decade and has been suggested to be an important effector mechanism for IFN's antitumor effects in the treatment of cancer. The aim of this review is to summarize and discuss the recent data in the field of type I IFN-induced apoptosis, with special emphasis on the molecular mechanisms of apoptosis and on the role of alternative noncanonical signaling pathways stimulated by type I IFNs in this process.