Summary Background Loss of response to anti-TNF agents in Crohn's disease is an emerging clinical problem. Aim To review the causes, incidence and management approach of loss of response. Methods A search of medical database (PubMed) and of meetings' proceedings for definitions, causes and incidence of loss of response was carried out. Personal correspondence with principal investigators was conducted to retrieve missing data. Results Various definitions of loss of response abound, hampering the ability to assess accurately the magnitude and management of this clinical problem. We propose to distinguish between a clinical worsening on anti-TNF treatment and a true loss of response to anti-TNFs. Accordingly, loss of response to anti-TNFs at 12 months of therapy occurs in 23-46% of patients when judged by dose intensification, or 5-13% when gauged by drug discontinuation rates. The management of loss of response should allow for a period of watchful waiting as quite often the patients' symptoms may resolve without alteration of therapy. If they do not, then identifying the correct mechanism responsible for clinical deterioration is prudent. Once symptoms are ascertained to arise from inflammatory IBD activity, drug level and antidrug antibody measurement can then help distinguish between non-adherence to therapy, immunogenicity and non-immune clearance of anti-TNF, or an un-chequered inflammation despite adequate anti-TNF levels. The latter finding may be best addressed by a switch to another class of immunomodulators, whereas a low drug level should probably be managed by dose intensification or a switch to another anti-TNF. Conclusion Studies defining how best to translate drug-level monitoring and other mechanistic considerations into clinical decisions are urgently needed.