Derived from the historical molecule sulfasalazine, mesalamine has remained one of the mainstays for treatment of inflammatory bowel disease in the last 50 years. Recent advancement in both clinical and basic research has led to reappraise the drug under two crucial aspects. Firstly, there has been a re-evaluation of the chemo-protective effect of mesalamine against sporadic colorectal cancer. Evidence that inflammation plays a strong role in tumor induction from one side, and demonstration that mesalamine can touch on specific molecular steps enhancing apoptosis on the other side have re-shaped the indications of mesalamine for ulcerative colitis. Secondly, the role of thiopurines (azathioprine and 6-MP) in the maintenance of remission of ulcerative colitis has been reiterated by the results of several clinical trials. During attempts at clarifying the reasons why certain patients appear to be resistant to thiopurines, it was interestingly found that mesalamine can interfere thiopurine metabolism, causing an increased blood concentration of the specific immunosuppressive metabolites and a sequential enhancement of drug effectiveness. Mesalamine is therefore being studied as a means to overcome the genetically determined resistance to thiopurines. Such sharpened indications have reiterated attention to correct dosing: the results of controlled trials have shown mesalamine to be fully effective at twice the traditional daily dosage (4.8 grams instead of 2.4). The attendant problems of compliance seem to find solution in the availability of multi-matrix system formulations. This mesalamine story reminds us that in the absence of an etiological target capable to guide research to trace one abrogating molecule, (as it has happened for viral hepatitides for example), treatment of inflammatory bowel disease remains anti-inflammatory in nature and thus multifaceted. Besides justified use of cutting-edge technology to find novel molecules, smart re-evaluation of what is already in our hands can sometimes bring about unexpected breakthroughs.