The introduction of steroid therapy by Truelove and Witts in the 1950s revolutionized the treatment of ulcerative colitis. Corticosteroids are potent inhibitors of T-cell activation and proinflammatory cytokines and still represent the mainstay of therapy of patients with ulcerative colitis. About 15% of patients are resistant to steroids, and about a quarter of patients become dependent within 1 year of therapy. Steroid-related adverse events are numerous and occur frequently. So, new steroids with low systemic absorption and better safety profile have been studied, but they show an overall lower efficacy compared with traditional steroids. A new drug-delivery system based on the use of autologous erythrocytes loaded with dexamethasone 21-phosphate has been recently developed. Several studies have demonstrated its efficacy in steroid-dependent patients leading to complete withdrawal of oral steroids and disappearance of the most steroid-related adverse events. In this review we elaborate on the role of steroids in the treatment of ulcerative colitis, focusing on the aspects related to the mechanisms of action and resistance to the steroids, and their secondary effects. Moreover, we analyse the alternatives to traditional systemic steroids such as the new steroids with low bioavailability and the steroids encapsulated into erythrocytes.