Models for in vivo scenarios of transcellular biosynthesis provide invaluable information about the regulation of eicosanoid biosynthesis that is likely to occur during multicellular events in vivo. The experimental approach of studying eicosanoid generation during cell-cell interactions and receptor-mediated cell activation represents a significant advancement beyond initial observations of eicosanoid formation and bioaction in isolated cell types that were activated under less physiologically relevant conditions. The experimental models reviewed in this chapter should be viewed as specific examples or as approaches to the study of cell-cell interactions. These examples may serve as guidelines to investigate novel cell-cell scenarios (see Fig. 3) and advance the emerging area of transcellular biosynthesis of bioactive lipid mediators.