Tumor Necrosis Factor α (TNF) is a significant systemic inflammatory cytokine in several immune-mediated inflammatory diseases (IMIDs) including inflammatory bowel disease (IBD, Crohn's disease (CD), and ulcerative colitis) and was the first target approved for biologic therapy in IBD. This article reviews the efficacy and safety of antiTNF agents for the treatment of CD including specific conditions (e.g. perianal fistula, prevention of post-operative recurrence), and practical approaches to managing antiTNF therapy (e.g. combination with immunosuppressants, early introduction of antiTNF treatment, and therapeutic drug monitoring (TDM)). This review is based on data from randomized controlled trials, real-world evidences and comparative studies gathered over the past 25 years. Anti-TNF agents have revolutionized treatment of IBD and other IMIDs. Early introduction of treatment, concurrent use of immunomodulators, and TDM are associated with improved clinical outcomes. Anti-TNF agents are preferred for subpopulations of CD including patients with perianal CD, extraintestinal manifestations, and postoperative prevention of CD. Biosimilars have increased access to anti-TNF agents and lowered overall costs. Future studies are needed to determine which agents are most likely to be efficacious and safe for subpopulations with CD.