5-aminosalicylic acid (5-ASA) is the standard first-line treatment for mild-to-moderate ulcerative colitis. A variety of 5-ASA delivery systems are available and in development, including both oral and rectal formulations; all of which aim to deliver the active drug to the colon while minimizing systemic absorption. Because the efficacy of most oral 5-ASA therapies is broadly similar, the appropriate selection of a given formulation often relies on other factors. This article explores the differences between oral 5-ASA formulations in terms of their delivery system, reviews the available data on oral 5-ASA treatment efficacy and tolerability, and examines the rationale for changing from one 5-ASA formulation to another if a patient does not respond to, or worsens on, their existing agent.