Three oral disease-modifying drugs-fingolimod, teriflunomide, and dimethyl 
fumarate (DMF)-are available for treatment of relapsing forms of multiple 
sclerosis (MS). All three agents were approved in the last decade, primarily on 
the basis of a moderate to substantial reduction in the occurrence of MS 
relapses and central nervous system lesion formation detected by MRI. In the 
trials leading to approval, the first oral disease-modifying drug, fingolimod, 
reduced the annualized relapse rate (ARR) from 0.40 in placebo-treated patients 
to 0.18 (FREEDOMS) and from 0.33 in patients treated with interferon β1a 
intramuscularly to 0.16 (TRANSFORMS). Teriflunomide, approved on the basis of 
the two placebo-controlled trials TEMSO and TOWER, demonstrated a reduction in 
the ARR from 0.54 to 0.37 and from 0.50 to 0.32 respectively. The latest oral MS 
medication, approved in 2014, is DMF, which had been used in a different 
formulation for treatment of psoriasis for decades. In the 2-year DEFINE study, 
the proportion of patients with a relapse was reduced to 27 %, compared with 46 
% in placebo arm, whereas in the CONFIRM trial, the ARR was reduced from 0.40 
(placebo) to 0.22 in the DMF-treated group of patients. In this review, we will 
elucidate the mechanisms of action of these three medications and compare their 
efficacy, safety, and tolerability as a practical guideline for their use. We 
will further discuss effects other than relapse reduction these small molecules 
may exert, including potential activities within the central nervous system, and 
briefly summarize emerging data on new oral MS drugs in clinical development.