Although all structural studies on cytokine–cytokine receptor interactions are based on a crystallized cytokine binding to its specific receptor, there is no dearth of evidence that membrane-embedded cytokines are biologically active by virtue of cell–cell contact. Clearly the orientation of the membrane cytokine is such that it allows binding to the receptor, as takes place with the soluble form of the cytokine. In this issue, Bellora et al. [Eur. J. Immunol. 2012. 42: 1618–1626] report that interleukin-18 (IL-18) exists as an integral membrane protein on M-CSF-differentiated human macrophages and that upon LPS stimulation, IL-18 induces IFN-γ from NK cells in a caspase-1-dependent fashion. The immunological and inflammatory implications for this finding are considerable because of the role of IL-18 as the primary IFN-γ inducing cytokine in promoting Th1 responses.