The treatment of IBD with anti-TNF agents has substantially evolved since their first introduction more than a decade ago. The robust efficacy witnessed in many patients has raised new questions pertaining to the observation of subgroups of patients who fail to respond or who lose response to these otherwise very effective drugs. Conversely, the exorbitant cost of biologic agents coupled with their efficacy in inducing lasting remission has introduced new concepts addressing the possibility of therapy cessation in some patients after deep remission has been achieved. Measuring drug and anti-drug antibody (ADA) levels which develop in some patients has emerged as a valuable tool in understanding the mechanisms responsible for some of these clinical scenarios. However, knowledge on how to use these measurements to guide clinical decisions in daily practice is still in its nascency and awaits prospective validation trials. Furthermore, as described in this Review, knowledgeable interpretation of drug and ADA test results mandates understanding the interplay between the technical profile of the assay used, the timing of the measurement in the drug cycle, assessment of disease activity, and the profoundly different pharmaco-clinical scenarios that can culminate in a similar test result.