Ulcerative colitis is a chronic condition that requires long-term treatment. The first-line therapy remains 5-ASA, which is available in a variety of different formulations and dosing schedules. Multiple studies have demonstrated that adherence rates to prescribed 5-ASA products is below what would have been expected with significant consequences for important outcomes. Worse disease outcomes, higher medical costs, and even potentially higher rates of colorectal cancer have been associated with nonadherence. Nonadherence is multifactorial, fluid in nature over time, and dependent on disease activity level. Interventions to improve adherence rates have to be individualized. With the advent of simpler dosing regimens it was assumed that adherence rates would improve, but this has not necessarily been the case. Despite our current knowledge about nonadherence, it remains difficult to manage in the long term.