Inositol phosphates and inositol pyrophosphates are small molecule metabolites that play important roles in nuclear processes such as transcription control, mRNA export and DNA repair. On this wonderful occasion of the fiftieth anniversary of the Advances in Enzyme Regulation conference, it is a privilege to participate through presenting recent developments in the area of inositol phosphate and pyrophosphate regulatory biology. This article summarizes recent advances in understanding IPs and PP-IPs biology in development and nuclear cell signaling. Data obtained from various model organisms hint at the emerging modes of mechanisms of these versatile molecules. Studies in model organisms revealed that IPs and PP-IPs are critical for development and signaling in plants, mice, zebrafish and slime mold. In plants, IP molecules are required for signaling in response to stress, hormone, and nutrient, by transcriptional regulation of the stimuli-responsive genes. In some cases, IPs act as regulatory molecules as the levels of IPKs/IPs are induced by those stimuli and a constitutively induction of downstream events can be accomplished by over-expressing the IPKs. Nutrient sensing is a recurring theme in IP biology as IPs and PP-IPs are also involved in amino acid and phosphate signaling in yeast and possible glucose sensing in pancreatic β cells, indicating it maybe acquired early during evolution. There are some newly discovered nuclear roles of IPs: 1) binding to and possibly regulation of the SCFTIR1 ubiquitin ligase complex, and 2) RNA editing by acting as structural co-factor of ADAR2 and ADAT1. On the other hand, IPs and PP-IPs are also implicated in some novel non-nuclear processes: 1) insulin secretion, 2) negative regulation of PIP3 signaling and 3) modulation of intracellular Ca2+ concentration. Following the discovery of new biological roles of IPs and PP-IPs, a few new receptors for IPs and PP-IPs were identified in the process. Three modes of receptor binding by IPs and PP-IPs can be summarized: 1) Direct binding to the receptor (e.g. TIR1), 2) displacement of a ligand (e.g. PIP3) already bound to the receptor (e.g. PH domain containing proteins, and 3) acting as a structural co-factor and possibly incorporated inside the receptor during protein folding (e.g. ADAR2). Hopefully, more experimentation will uncover more receptors for and biological roles of these versatile molecules.