In recent decades the structure and the function of interferons (IFNs) have been elucidated and it is now clear that IFN is not only a protein but a group of proteins with parallel, but not analogous or identical, biochemical and biological properties. Among them there are at least 12 subtypes of IFN-alpha which are all involved in the control of several cellular functions and are all actively engaged in host defence mechanisms against infections. These acquisitions led to the clinical use of different types of IFN-alpha with appreciable success in several diseases. There are however several possibilities to optimize IFN-alpha treatment which can and must be addressed. For instance, as regards IFN-alpha biology and therapy issues, we need to understand how the different subtypes can generate similar signalling outputs but also govern specific cellular responses and more in general why the body produces so many of these IFN-alphas. This paper highlights the complexity of the IFN-alpha system and tries to summarize what is currently known of the distinctive properties of each individual IFN-alpha subtype. The data presented on the functional distinctions between IFN-alpha subtypes suggest that the commercially available IFN-alpha preparations may differ in some biological, pharmacological and therapeutic aspects and that a wiser and more prudent use of the different IFN-alpha preparations may provide more therapeutic benefits to patients.