While there is no cure for multiple sclerosis (MS), numerous disease-modifying drugs are now available to treat MS patients. In fact, the therapeutic strategies are now more and more complex, directly impacting the management of patients. Despite the good safety profile of the first-line immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain about the right timing to switch for a second-line agent and whether escalation therapy is an appropriate therapeutic strategy. In this review, we conducted a systematic search by PubMed using the terms: treatment, multiple sclerosis, therapeutic, DMT and treatment response. Randomized trials and reviews addressing MS, DMTs and management strategies were selected and included in this review. Herein, we present the currently approved and emerging drugs used for the treatment of MS with their relative benefit/risk profiles, and their respective positions in the therapeutic arsenal. We then focused on the different therapeutic strategies and criteria available to evaluate the response to disease-modifying therapies (DMTs).