Randomized trials support the use of the thiopurines and anti-TNF monoclonal antibodies in treating Crohn disease. New therapeutic approaches and laboratory assays have helped optimize the use of these agents. Thiopurine methyltransferase activity should always be determined to avoid thiopurines in individuals with absent enzyme activity. The role of metabolite-adjusted dosing when initiating thiopurines is not settled. Measuring metabolites helps guide management in patients failing therapy. Loss of response to anti-TNF therapy is mitigated by maintenance therapy and concomitant immunomodulators. When loss of response to infliximab occurs, management is guided by the serum concentrations of infliximab and antibodies to infliximab.