Tumor necrosis factor (TNF) is a major mediator of innate and adaptive immunity and has become an important therapeutic target for controlling inflammation. However, TNF is highly pleiotropic, with distinct actions on different cell types and the net effects are often complex, making it difficult to predict the responses to TNF or to anti-TNF therapies on particular organs or in particular diseases. Rodent models have had only limited success in predicting human responses. Experimental medicine studies in humans can pose ethical and logistic issues, whereas studies using cultured human cells may be misleading because of alterations in cell phenotype resulting from the loss of anatomic relationships to other cells and extracellular matrix combined with stimuli provided by non-physiological factors such as serum and contact with tissue culture plastic that may alter responses to TNF. Here we   present examples from our own experiments to demonstrate that human organ culture can be effectively utilized to study TNF effects on different cell types in a manner that preserves their proper anatomic relationships and better reflects in vivo responses. Aspects amenable to study with this approach include basal and regulated TNF receptor expression, activation of specific TNF signaling pathways and a variety of biological and immunological responses that may predict patient outcomes.