This review centers around seven IMIDs (rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, psoriasis, atopic dermatitis, and asthma) with substantial unmet medical needs and sheds light on the signaling mechanisms, disease relevance, and evolving drug development activities for five TNF/TNFR signaling axes that garner substantial drug development interest in these focus conditions. This evidence concerns the gene TNF and rheumatoid arthritis.