The inositides are key cellular second messengers with well established roles in signal transduction pathways initiated by cell surface receptor activation. The recent identification of an evolutionarily conserved nuclear signaling pathway for higher inositol polyphosphates has defined a new signaling paradigm for this diverse class of molecules whose biosynthesis and regulation is mediated by what are likely some of the earliest ancestors of the inositide kinase families. Inositol polyphosphate multikinase (IPMK) represents the most catalytically diverse member of this family with critical roles in nuclear functions including mRNA export, transcriptional regulation, and chromatin remodeling.