Interferon (IFN) beta was the first disease-modifying therapy (DMT) available to treat multiple sclerosis (MS), providing patients with a treatment that resulted in reduced relapse rates and delays in the onset of disability. Four IFN beta drugs are currently approved to treat relapsing forms of MS: subcutaneous (SC) IFN beta-1b, SC IFN beta-1a, intramuscular IFN beta-1a, and, most recently, SC peginterferon beta-1a. Peginterferon beta-1a has an extended half-life and requires less frequent administration than with other available treatments (once every 2 weeks vs. every other day, 3 times per week, or weekly). Large, randomized controlled clinical trials have confirmed the efficacy of IFNs for treatment of relapsing MS. The most frequent adverse events experienced by patients receiving IFNs include injection site reactions (ISRs) and flu-like symptoms (FLS). Patient education and mitigation strategies are key to managing ISRs and FLS and supporting therapy adherence. With fewer injections needed, peginterferon beta-1a is associated with less frequent discomfort, which may translate to improved adherence, a major factor in treatment efficacy. Because the available IFN therapies differ in administration route and frequency of injection, switching among these therapies may be a viable option for patients who experience issues with tolerability. While there are now a number of DMTs available to treat relapsing MS, the efficacy and long-term safety profile of IFNs make them an important first-line option for treatment.