5-Aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once daily mesalazine formulations.