Interferons alpha (IFNs-alpha) are pleiotropic cytokines belonging to the type I IFN family, originally described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer and viral diseases. Notably, certain autoimmune disorders have been postulated to be mediated by endogenous IFN-alpha and are often observed in some IFN-treated patients. IFN-alpha can induce multiple biological effects, including induction/promotion of apoptosis and inhibition of cell growth. In addition, these cytokines promote the differentiation and activity of host immune cells. Early studies in mouse tumor models showed the importance of host immune mechanisms in the generation of a long-lasting antitumor response after injection of the animals with either IFN or tumor cells genetically modified for IFN-alpha production. Several studies have shown that IFN-alpha can induce the rapid differentiation of monocytes into highly activated dendritic cells (DCs). Of note, these DCs (IFN-DCs) are particularly effective in taking up complex antigens and inducing T- and B-cell immunity. The ensemble of these results suggests that IFN-DCs can play a role in the generation of antitumor T-cell immunity, pointing out that these cells could be successfully used in strategies of cancer immunotherapy. Likewise, IFN-alpha-DC interactions could also play a role in the pathogenesis of some autoimmune disorders, often associated with IFN-alpha treatment. All this reveals the complexity of the IFN-alpha-DC interactions under normal and pathological conditions and stimulates further studies for identifying optimal modalities in either using these cytokines or controlling their production/action in patients.