Disease-modifying therapies for multiple sclerosis (MS) are a mainstay of treatment. All of these agents are associated with side effects, most of which are easily managed with only minimal additional pharmacotherapy. Appropriate patient education and physician support are critical to achieve the best medical outcome and to maximize patient compliance with long-term therapies for this debilitating condition. Although many side effects subside shortly after initiation of treatment, such as flu-like symptoms with interferon treatment, some side effects are cumulative and can become life-threatening if they are unrecognized (e.g., cardiotoxicity with mitoxantrone). Therefore, physicians must be aware of appropriate laboratory monitoring schedules to prevent serious toxicities and to become familiar with less serious but more common side effects that often threaten patient compliance. Patients should be encouraged to communicate with their physicians so that side effects can be managed promptly. This article describes and provides management strategies for side effects associated with MS treatments.