Tumor necrosis factor (TNF) inhibitors have been established as therapeutic agents for treating refractory systemic rheumatic diseases including rheumatoid arthritis and ankylosing spondylitis. While TNF inhibitors can effectively decrease the inflammation, they also decrease resistance to infection and affect immune surveillance mechanisms. Clinicians are sometimes faced with special situations such as chronic hepatitis B infection, pregnancy, complicated medical problems and older populations when prescribing TNF inhibitors. These conditions are affected by TNF inhibitors, which may induce poor clinical outcomes as well as side effects. To date, there are limited clinical data and recommendation guidelines on patients receiving TNF inhibitors in these special situations. We reviewed the effect of TNF inhibitors on each condition with review of the literatures concerning the clinical trials of TNF inhibitors in various rheumatic conditions. TNF inhibitors should be introduced carefully in special situations affecting the outcome of underlying illness, depending on the risk/benefit profiles in each case.