The cytokine interferon (IFN)-β is successfully used in the treatment of multiple sclerosis. However, some patients fail to respond to therapy, probably due to different biological patterns that are of importance in influencing clinical response. A common mechanism involved in the modulation of responsiveness to cytokine is represented by regulation of their receptor expression through autocrine-ligand-mediated loops. Mechanistically, IFN-β exerts its biological effects through interaction with the IFN-α/-β-receptor (IFNAR), which then activates several transcription factors. IFNAR is composed of 2 chains, IFNAR-1 and IFNAR-2, which associate with IFN-β to form a ternary complex. The major ligand-binding subunit is IFNAR-2 and it exists in 3 mRNA splice variants, resulting in 2 transmembrane (IFNAR-2b and IFNAR-2c) isoforms and a soluble (IFNAR-2a) one. On the contrary, from normal cells only one IFNAR-1 isoform, with transcriptional capacity, was identified. In the past decades, considerable information has accumulated pertaining to the downregulation of the IFNAR complex in IFN-treated patients, but only a few studies have investigated the molecular events involved in this phenomenon. The intent of the present review is to place this receptor downregulation in the context of IFN-β therapy and of its clinical and biological outcomes in IFN-β-treated patients.