Although we have been living in the era of biologic therapy for several decades, the use of immunomodulators (primarily thiopurines [azathioprine and mercaptopurine] and less so methotrexate) still remains an important component of the inflammatory bowel disease (IBD) pharmaceutical arsenal. Thiopurines as monotherapy exert corticosteroid-sparing effects and can maintain long-term remission in a considerable proportion of patients who have frequent relapses and are or have become mesalazine and/or corticosteroid intolerant or refractory. Withdrawal of thiopurines results in relapse of disease in a significant proportion of patients. Thiopurines enhance the induction effect of anti-TNFα biologics and can reinstate disease remission in patients who lose response to anti-TNF monotherapy. In thiopurine-naïve ulcerative colitis (UC) patients with iv corticosteroid-refractory disease, thiopurines offer an excellent maintenance strategy after cyclosporine rescue therapy. They also prevent the postoperative recurrence of Crohn's disease, especially in smokers, and can achieve response or remission in uncomplicated perianal fistulizing disease. Close monitoring of patients with sequential measurements of complete blood count, liver enzymes, serum and fecal biomarkers, and/or thiopurine metabolites is essential to assess efficacy, safety, and adherence to treatment. Adverse reactions are dose dependent or idiosyncratic. Idiosyncratic reactions to azathioprine, except pancreatitis, can be treated by switching to mercaptopurine or 6-thioguanine. Thiopurines increase the relative risk for skin, urinary tract, and lymphoid tissue malignancies but the absolute risk is low. Preventive measures include sunlight protection and annual Pap smears (females). The use of antimetabolite therapy in patients over the age of 65 years is generally avoided. Methotrexate has advantages over thiopurines subsequent to its once weekly dosing, faster onset of action, and better safety profile relating to malignancies; however, its parenteral administration, contraindication in pregnancy and lactation, and its misconceptions particularly related to hepatotoxicity have reserved its use as a second-line therapy, i.e., when thiopurines fail. Yet, methotrexate in combination with a tapering dose of corticosteroids is an effective agent for active luminal Crohn's disease. In combination with infliximab is preferred for pediatric patients and adolescent IBD male patients who have not contracted the Epstein-Barr virus. Methotrexate also reduces the immunogenicity of infliximab. Folic acid supplementation and close monitoring with blood tests and renal and liver function tests are essential to prevent toxicity especially in patients with diabetes mellitus, non-alcoholic liver fatty disease (NAFLD), malnutrition, and renal function impairment.