Ulcerative colitis is a chronic immune-mediated inflammatory disease of the colon that causes considerable morbidity and increases the risk of colorectal cancer. Several targeted therapies have been developed for moderate-to-severe ulcerative colitis, significantly improving its management. Ozanimod and etrasimod, oral small-molecule drugs, are the latest addition. They belong to the class of sphingosine-1-phosphate receptor (S1PR) modulators and are the first members of this class to be granted approval for ulcerative colitis. They act by blocking lymphocyte trafficking from lymph nodes to inflamed tissues without impairing other immune system functions. This narrative review summarizes current knowledge of sphingosine-1-phosphate receptor modulators, focusing on safety. Safety data from the field of multiple sclerosis (MS) will be discussed because the first S1PR modulator to reach the market, fingolimod, was used extensively for relapsing-remitting MS. Indications for the safe use of ozanimod and etrasimod in ulcerative colitis patients will be provided.