As a complex group of naturally occurring proteins and glycoproteins produced by different human cells, interferons (IFN's) have initially been detected as the first line of defense in the natural course of viral infection. Due to their antiproliferative, differentiation-inducing and immunmodulatory properties they also were considered important new drugs in the treatment of cancer. The introduction of recombinant DNA technology in the late 1970's permitted large-scale production of highly purified substrates enabling systematic clinical investigations. After several decades of interferon research there have been peaks and troughs in estimating their therapeutical value. Today the abundant data figure as parts of a giant puzzle which have to be assembled. The identified molecular structure of IFN-alpha2b may serve as a basis for future IFN drug design. The profound knowledge of the endogenous IFN system and its pathological disturbances in the natural course of chronic diseases is a 'conditio sine qua non' to explain seeming inconsistency as e.g. the 'paradox' role of IFN-alpha in HIV-infection. A better understanding of the pathophysiologic function of the acid-lability inducing antigen (ALIA) and the physiologic role of the IFN-type I induced Mx protein will be helpful on this way. IFN signal transduction via the Jak-STAT system reveals mechanisms of action within hematological disorders. In these terms, further developments in interferon therapy as well as future design of IFN substrates have to apply a strict standard. The article critically reviews to which extent actual treatment strategies as the application of IFN-inducers, consensus IFN as well as pegylated IFN's fit into therapeutic schedules which have to take into account all these novel insights.