Interferon beta preparations are the most widely used initial therapies prescribed for patients with relapsing–remitting multiple sclerosis. Phase III studies have demonstrated comparable efficacy on clinical measures of disease activity, variable benefits on radiological measures, and good overall tolerability. Subsequent clinical studies have attempted to compare directly the three available interferon beta preparations, reporting both safety and efficacy data. We review the literature on studies evaluating interferon beta therapy for patients with relapsing–remitting multiple sclerosis, discuss reasons for discrepant findings, and assess the utility of interferon beta-based combination regimens as the focus of future studies in the increasingly complex multiple sclerosis therapy landscape.