Background Ulcerative colitis (UC) is characterised by chronic mucosal inflammation primarily in the colon. Guidelines recommend mesalazine as first-line therapy for induction of maintenance in mild-to-moderate Ulcerative colitis. Patients' preferences, response to treatment, site and extent of inflammation and cost are important considerations when selecting mesalazine therapy. Aims/Methods This article reviews mesalazine's role in ulcerative colitis and explores the factors to consider when optimising mesalazine-based therapy. Findings Up to two-thirds of patients fail to respond to induction therapy within 8 weeks, thereby prompting a switch of formulations or escalation to oral corticosteroids. While there are no major variations in efficacy, different mesalazine formulations are not interchangeable because of differences in mode of drug delivery, site of drug release and excipients. Switching mesalazine products before escalating therapy may, therefore, spare patients from wider side effects and higher costs. Conclusions Optimising mesalazine-based therapy requires individualised treatment plans based on patient preferences, site and extent of inflammation, response to treatment and potential side effects. An algorithm exists to guide the selection of alternative mesalazine formulations when required.