Polyphosphoinositides (PPIn) are low-abundance membrane phospholipids that each bind to a distinctive set of effector proteins and, thereby, regulate a characteristic suite of cellular processes. Major functions of phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2 ] are in membrane and protein trafficking, and in pH control in the endosome–lysosome axis. Recently identified PtdIns(3,5)P 2 effectors include a family of novel β-propeller proteins, for which we propose the name PROPPINs [for β-propeller(s) that binds PPIn], and possibly proteins of the epsin and CHMP (charged multi-vesicular body proteins) families. All eukaryotes, with the exception of some pathogenic protists and microsporidians, possess proteins needed for the formation, metabolism and functions of PtdIns(3,5)P 2 . The importance of PtdIns(3,5)P 2 for normal cell function is underscored by recent evidence for its involvement in mammalian cell responses to insulin and for PtdIns(3,5)P 2 dysfunction in the human genetic conditions X-linked myotubular myopathy, Type-4B Charcot–Marie-Tooth disease and fleck corneal dystrophy.