To help define the molecular basis of cellular signalling cascades, and their biological functions, there is considerable value in utilizing a high-quality chemical ‘probe’ that has a well-defined interaction with a specific cellular protein. Such reagents include inhibitors of protein kinases and small molecule kinases, as well as mimics or antagonists of intracellular signals. The purpose of this review is to consider recent progress and promising future directions for the development of novel molecules that can interrogate and manipulate the cellular actions of inositol pyrophosphates (PP-IPs)–a specialized, ‘energetic’ group of cell-signalling molecules in which multiple phosphate and diphosphate groups are crammed around a cyclohexane polyol scaffold.