Interferon-beta (IFN-β) is one of the main first-line disease-modifying drugs indicated for the treatment of multiple sclerosis (MS). The drug exhibits only limited effectiveness, and does not produce clinical benefits in around 20%-50% of patients. The availability of biomarkers would be beneficial for identification of patients at high risk of treatment failure, before initiation of therapy. Over the last 5 years, the search for such biomarkers has intensified and various promising candidates have been uncovered. Here, we review the main attempts undertaken to identify polymorphic variants associated with response to IFN-β therapy in MS by means of candidate gene approaches and whole-genome association scans. Despite substantial progress made in the field, there is still a long way to go before biomarker discoveries can be incorporated into clinical practice to predict IFN-β-responder status in MS patients.