Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphosphate (IP₆) to generate the pyrophosphate IP₇. Initial insights into functions of these substances derived primarily from yeast, which contain a single isoform of IP₆ kinase (yIP₆K), as well as from the slime mold Dictyostelium. Mammalian functions for inositol pyrophosphates have been investigated by using cell lines to establish roles in various processes, including insulin secretion and apoptosis. More recently, mice with targeted deletion of IP₆K isoforms as well as the related inositol polyphosphate multikinase (IPMK) have substantially enhanced our understanding of inositol polyphosphate physiology. Phenotypic alterations in mice lacking inositol hexakisphosphate kinase 1 (IP₆K1) reveal signaling roles for these molecules in insulin homeostasis, obesity, and immunological functions. Inositol pyrophosphates regulate these processes at least in part by inhibiting activation of the serine-threonine kinase Akt. Similar studies of IP₆K2 establish this enzyme as a cell death inducer acting by stimulating the proapoptotic protein p53. IPMK is responsible for generating the inositol phosphate IP₅ but also has phosphatidylinositol 3-kinase activity--that participates in activation of Akt. Here, we discuss recent advances in understanding the physiological functions of the inositol pyrophosphates based in substantial part on studies in mice with deletion of IP₆K isoforms. These findings highlight the interplay of IPMK and IP₆K in regulating growth factor and nutrient-mediated cell signaling.