The inflammatory cytokine tumor necrosis factor (TNF), as well as most other ligand members of the TNF superfamily, exist both as classical soluble cytokines, but also in the form of type II transmembrane proteins. Both forms possess bioactivity, although some effects are distinct. In addition, an increasing body of evidence suggests that the membrane integrated ligands can receive signals, i.e. act as receptors which can transmit positive and negative feedback signals into the ligand bearing cell. Thus, reverse signaling enables a two-way communication in cell-to-cell signaling, and it is conceivable that this bi-directional signal exchange contributes to the plasticity of the ligand-receptor systems. Reverse signaling mainly has been observed in the immune system and within the TNF superfamily. Its function is only beginning to emerge warranting additional investigation, especially when it comes to therapeutic strategies involving cytokine modulation. This review provides an update of the literature about reverse signaling of transmembrane TNF family members and discusses its potential biological and clinical impact.