Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B-lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1–2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T-cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity.