"Endocytosis is subject to extensive and complex regulation and has a major role in cell signaling, cell-cell communication, and interactions between cells and their environment. In this issue [of Cell], Liberali et al. present a comparative, unbiased, and quantitative study of regulatory interactions between signaling, membrane traffic, and the cytoskeleton. They develop a hierarchical map of regulatory genetic interactions in membrane trafficking based upon their discovery of emergent properties of the endocytic membrane system and the evolution of its complexity as well as distinct regulatory programs that control subsets of endocytic activities and organelles. Cover artwork created by Lavinia Liberali and Luca Pitoni.” Via.