Mitoxantrone is a member of the anthracendione family developed to treat malignancies and increasingly used to treat multiple sclerosis (MS). It has been studied as a treatment for MS since the late 1980s, and is licensed in a number of countries for progressive and worsening MS. Review of the published earlier open-label, and more recently of controlled trials suggests that mitoxantrone is efficacious in cases of worsening MS that have an inflammatory component as evidenced by progression with or without superimposed relapses and/or gadolinium (Gd) enhancing magnetic resonance (MR) lesions. Today there is no robust evidence of efficacy in primary progressive MS or in later stages of secondary progressive MS beyond an EDSS score of 6. Relevant immunomodulatory mechanisms act both on T- and B-cell function, and mitoxantrone has selective immune effects in MS by decreasing levels of TNF-alpha, IL-2, IL-2R-beta1, IL-10 and IFN-gamma. Adverse events include nausea, alopecia, infections, menstrual disorders, risk of cardiotoxicity and malignancy. Different regimens are used according to different regulatory demands in different countries. The two most commonly used regimens are every 3 months intravenous (i.v.) 12 mg/m2 for 2 years or 20 mg mitoxantrone (i.v.) combined with 1 g methylprednisolone (i.v.) every 4 weeks for 6 months. The cumulative life dose in MS patients is 140 mg/m2. Mitoxantrone is currently used as a second line drug in MS patients whose disease is not controlled by beta-interferon or glatiramer acetate. In this review, we will discuss the clinical disease patterns of MS patients who are most likely to benefit from mitoxantrone, its magnitude of clinical effect, and limitations of using mitoxantrone in MS. Mitoxantrone as a second line therapy in non-responders of beta-interferon and glatiramer acetate will be assessed. Recent strategies of combination therapy, and the optimal dose regimen will also be discussed.